Therapeutic compounds and methods

Abstract

Novel compounds such as DHMP maintain DHM features and pharmacological activities with increased potency and efficacy, improved water solubility, enhanced bioavailability, increased permeability to the blood brain barrier (BBB), and increased stability. Because DHMP retains the therapeutic activities of DHM and has properties that improve its bioavailability, it can be used as a therapeutic agent for treating Alzheimer's disease-related diseases (ADRD) including Alzheimer's disease (AD), Vascular Dementia, Frontotemporal Dementia (FTD), Mixed Dementia as well as neurodegeneration such as Parkinson's disease. Administration of these compounds result in beneficial pathological changes including reduction of Aꞵ and Tau, improvement of neuroinflammation, reduction of cognitive / memory deficits, as well as improvement of anxiety, depression, and aggression. The disclosed DHM derivatives can also be used to treat sleep disorders, neurological disorders such as PTSD, Autism, Epilepsy / Seizures, and Alcohol Use Disorders (AUD), fetal alcohol syndrome (FAD), substance addictions, and cancers.

Description

[0001] THERAPEUTIC COMPOUNDS AND METHODS

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Nos. 63 / 578,303 filed August 23, 2023, 63 / 657,008 filed June 6, 2024, and 63 / 677,247, filed July 30 2024, which applications are incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] Dihydromyricetin (DHM), a natural flavonoid compound extracted from Hovenia and Rattan tea, has been widely used in the supplement market due to its various health benefits. We have demonstrated that DHM is a positive modulator of GABAergic transmission and an anti-inflammatory agent.

[0006] Gamma-aminobutyric acid (GABA) is a neurotransmitter in the bram that helps calm the nervous system and organize sensory input. Imbalances in GABA activity can lead to various neurological and mental health issues including anxiety, PTSD, depression, epilepsy / seizures, Huntington's disease, autism, ADHD, and drug / alcohol dependence. Low GABA levels can affect concentration and memory, and dysfunction in the GABAergic system can cause cognitive impairments in Alzheimer's disease (AD). Unfortunately, GABAergic medications often lead to addiction, tolerance, and severe side effects.

[0007] Neuromflammation is a cntical process in diseases like AD, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). Patients with schizophrenia, depression, anxiety, bipolar disorder, obsessive-compulsive disorder (OCD), PTSD, and autism spectrum disorder (ASD) show significantly elevated cytokine levels However, effective anti- neuroinflammatory drugs are lacking.

[0008] We are the first to systematically explore DHM's therapeutic potential across various conditions, leveraging its GABA modulation and anti-inflammatory properties. These therapeutic effects include alcohol use disorder (AUD), fetal alcohol syndrome (FAS), epilepsy / seizures, and neurodegenerative diseases such as AD. Using modem molecular pharmacological approaches, we are also investigating DHM's potential for treating autism spectrum disorder (ASD).

[0009] As a natural compound, DHM has several limitations, including susceptibility to degradation and oxidation when exposed to air, light, and high temperatures, as well as low solubility, which affects its formulation. Therefore, developing variations of DHM with improved pharmacological properties would enhance its medical utility. SUMMARY

[0010] The present technology provides new compounds and compositions based on the natural product dihydromyricetin (DHM). We modified the parent compound DHM to provide new compounds that maintain and improve upon DHM's therapeutic properties. By modifying the DHM structure, we created compounds that not only maintain DHM’s original therapeutic properties, but also enhance the efficacy, are more stable, and minimize undesirable properties.

[0011] Accordingly, this disclosure provides a compound of Formula I: wherein

[0012] A is a direct bond, or A is NH, O, OP(=O)(OH)O , or (OCH2CH2)PO wherein p is 1-3; each R1is independently -(Ci-Ce)alkyl, -(Cs-Cejcycloalkyl, -(C=O)(Ci-Ce)alkyl, or H;

[0013] R2is -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, -(C=O)(Ci-C6)alkyl, or H;

[0014] R3is H, -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, or -(C=O)(Ci-C6)alkyl;

[0015] R4is nitrogen heterocycle, amino, guanidine, amino acid, or saccharide, each optionally substituted; or when A is NH, O, -OP(=O)(OH)O-, or -(OCH2CH2)PO-, R4is optionally H; and m is 0-8; or a pharmaceutically acceptable salt thereof. An R4moiety can be substituted by a substituent moiety described herein, for example, a -(Ci-Cio)alkyl such as methyl, ethyl, or straight-chain or branched - (C3-Cio)alkyl.

[0016] This disclosure also provides a composition comprising a compound described herein (e.g., a compound of Formula I); or an amino salt of dihydromyricetin, wherein optionally the amine moiety of the amino salt is piperidine, diethylamine, triethylamine, arginine, or lysine; and an excipient, a natural product, or a combination thereof.

[0017] Additionally, this disclosure provides a method for treating a subject in need of neuromodulation, which method comprises administering to the subject an effective amount of a compound or composition described herein to provide the neuromodulation.

[0018] The compounds or compositions of the present technology can be used in medical therapy. The medical therapy can be, for example, treating insomnia, sleep disorders, anxiety, declined cognition, impaired memory, and neurodegenerative diseases. The present technology also provides for the use of a compound or composition as described herein for the manufacture of a medicament to treat a condition or disease in a mammal, for example, a medicament to treat insomnia, anxiety, or neurodegeneration in a human. The medicament can include a pharmaceutically acceptable diluent, excipient, or carrier.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The following drawings form part of the specification and are included to further demonstrate certain embodiments or various aspects of the invention. In some instances, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention. However, one skilled in the art will understand that portions of the example or aspect may be used in combination with other examples or aspects of the invention.

[0021] Figure 1. Graph showing blood concentration of DHM and DHMP versus time.

[0022] Figure 2. Graphs showing DHMP potentiates GABAA receptors (GABAARS). DHMP is more potent and more efficacious than DHM.

[0023] Figure 3. DHM improves the neuronal synaptic pathological changes through the gephyrin- GABAAR pathway.

[0024] Figure 4. DHM reverses social isolation-induced anxiety. DHM effects on social isolation- induced anxiety-like behavior as measured by percentage of time spent A) in the open, B) closed arms, and C) the area between cross arms (called ‘intersection’) of elevated plus maze (EPM). *, p < 0.05 vs. vehicle control, f, < 0.05 vs. Iso2+Veh2, (n=6 / group, one-way ANOVA followed by multiple comparison Sidak method).

[0025] Figure 5. DHM restores hippocampal ATP levels and gephyrin protein expression levels induced by social isolation in mice. A) Social isolation resulted in reduced ATP levels in microdissected hippocampi (n=4). DHM restored ATP levels in hippocampi relative to controls and DZ treatment (n=4). B) Social-isolated mice exhibited decreased levels of gephyrin protein expression. DHM treatment reversed gephyrin protein expression at both 2 and 4-week isolation periods (n=4). *, p < 0.05 vs. vehicle control (G2+Veh2). f, p < 0.05 vs. Iso2+Veh2, one-way ANOVA followed by multiple comparison Sidak method.

[0026] Figure 6. DHM reduces the expression of SREBP-1, a pro-inflammatory marker expression. A) Representative Western blot image analysis of SREBP-1 in HepG2 and VL-17A cells cultured in ethanol and either untreated or treated with 5 pM of DHM for 24 hours. B) Representative WB of TNF- cc, IL-8, cleaved caspase-3, and P-actin in HepG2 and VL-17A cell lines.

[0027] Figure 7A-D. The effects of DHM on ethanol-induced pathology, hepatic mass, and metabolic signaling. C57BL / 6J male mice were provided access to a single bottle of 30% EtOH for a period of 6 weeks. A) H&E (hematoxylin and eosm) staining shows that DHM remarkably alleviated ethanol- induced lipid deposition (white arrows). B) Ethanol-fed mice had a larger liver mass compared against control (p<0.01; n=3). DHM administration at 10 mg / kg reduced the ethanol-mediated hepatic mass increase (**p<0.01; n=4), and both 5mg / kg and 10 mg / kg reduced triglyceride levels in the liver (p<0.01; n=4). E = EtOH, 5D = 5 mg / kg DHM, and 10D = 10 mg / kg DHM.

[0028] Figure 8. DHM reduces liver hepatoblastoma (HB) cell viability. HepG2 (A) and VL-17A (B) hepatoblastoma cell lines were exposed to 50 pM DHM for 24 hours and evaluated for cell viability using MTT. DEIM reduced the viability of both FIB cell lines after 24-hr exposure. 96-well plate seeded with 100,000 cells / well and repeated in triplicates (n=3); *p<0.05; student’s t-test.

[0029] Figure 9. DHM improves the quality of sleep in humans (IRB ID: UP-21-00653).

[0030] Figure 10. DHM improves the lung pathology induced by air PM 2.5 contamination for 24 hours in mice. The lung organs obtained from each group: A: Control, B: Contaminated group, C: Contaminated plus oral DHM (2mg / kg, once per day). The corresponding D-F were the pathological sections of lung organs obtained from each experimental group.

[0031] Figure 11. DHM dose-dependently inhibit H1N1 virus infection. Briefly, the nose-throat swab specimen method was used to induce infection and also collect samples for various respiratory tests, including the HINl / Swine Flu RT PCRtest.

[0032] Figure 12. DHM counteracts respiratory virus infection. The viruses include Rhinoviruses and influenza A or B virus. Briefly, the nose-throat swab specimen method was used to induce infection. The column in white is control group, the black column is the day 7 result of infected group, and the gray column is day 14 result of infection group. Dark column is the result in day 7 of infected +DHM group and light column was tested on day 14 in infected + DHM group.

[0033] Figure 13. DHM effects on seizures. A shows DHM (2 mg / kg oral) effects on overacting PTZ- induced seizures in rats . B shows DHM (5 mg / kg / day for 3 -month, oral) effects on relieving or reducing epilepsy seizures in Autism or epilepsy. *, p<0.05.

[0034] Figure 14. Image showing the Grid-walking test.

[0035] Figure 15. DHMP (D-P) improves stroke induced motor function deficits.

[0036] Figure 16. DHMP (D-P) improves novel object recognition and novel context recognition in TG-mice. A-B. Memory Test Protocol. C. Novel object recognition. D. Novel context recognition test. D-P treatment for TG-mice improved cognition / memory compared with age-matched, sucrose-treated TG-mice (n=6 / group), **p<0.00I, a one-way ANOVA followed by post hoc multiple comparison Tukey method.

[0037] Figure 17. DHMP treatment improves locomotor activity and reduces anxiety in TG-mice. Open field was used to measure locomotor activity. A Distance of movement. B Frequency of rearing. C Duration staying in the center. TG-mice showed inferred performance compared to wt control (n=5 mice). D-P treatment improved restored performance in TG-mice. D Anxiety in wt control, TG, and TG+D-P mice was measured by EPM (n=5 per group). Figure 18. Graphs showing evaluation of DHMP safety by oral DHMP daily at dosages of 1, 10, and 100 mg / kg using Functional Observational Battery (FOB) in Rats.

[0038] Figure 19. DHMP is safe for oral application every day in doses as high as 500 mg / Kg (Sprague Dawley (SD) rats). Toxic effects are not detected with basic metabolic tests.

[0039] Figure 20. Graph showing DHMP potentiates GABAARS dose-dependently in HEK293.

[0040] Figure 21. Offspring’s body weight, numbers of males and females (measured at P5).

[0041] Evaluating the safety of oral DHMP daily at dosages of 1, 10, and 100 mg / kg from 3rdtrimester (3rdweek) of pregnancy. GABAAR subunit compositions and functions are highly developmentally regulated during 3rdtrimester of pregnancy, with many subunit combinations expressed only postnatally. Therefore, we selected the time point of 3rdtrimester of pregnancy to evaluate DHMP safety on pregnancy in rats.

[0042] Figure 22. Graph showing DHMP effects on plasma [EtOH] BAC in SD-Rats.

[0043] Figure 23. Graphs showing DHMP effects on plasma [EtOH] BAC in human (IRB ID 2023LL01).

[0044] DETAILED DESCRIPTION

[0045] The present technology provides compounds comprising modifications of the DHM core structure shown below: 8

[0046] Dihydromyricetin (DHM), also known as Ampelopsin, is a flavonoid extracted from Hovenia dulcis and found in Ampelopsis, widely recognized for its diverse health benefits. My team has pioneered a systematic scientific investigation into DHM. We have conclusively shown DHM's role as a positive modulator of GABAARS.

[0047] Moreover, we are the first to systematically explore DHM's therapeutic potential across various conditions, including alcohol use disorder (AUD), fetal alcohol syndrome (FAS), and neurodegenerative diseases such as Alzheimer’s disease (AD), utilizing modem molecular pharmacological approaches.

[0048] In our studies related to AD, we observed that transgenic (TG) mouse models of AD display behavioral deficits akin to those seen in AD patients, including diminished exploratory locomotor activities, heightened anxiety, and susceptibility to seizures, alongside cognitive impairments. DHM administration effectively mitigates these psychological and behavioral deficits. Furthermore, we identified impairments in GABA release and dysfunction of GABAARS in hippocampal neurons from TG mice, which DHM restores. We also noted a decrease in gephyrin, a postsynaptic GABAAR anchor protein, in the hippocampus and cortex of TG mice, indicating loss of functional GABAARS and GABAergic synapses, pivotal in AD pathogenesis. DHM treatment restores gephyrm levels in TG mice by pharmacologically replenishing ATP levels, indicating restoration of gephyrm and GABAergic synaptic function as a potential mechanism underlying DHM's therapeutic effects. Normalization of gephyrin emerges as a novel target for AD treatment, underscoring DHM's promise as a therapeutic agent for AD.

[0049] In our alcohol-related studies, DHM was found to nullify single-dose ethanol intoxication- induced tolerance to ethanol itself, antagonize alcohol intoxication-induced GABAAR plasticity, and alleviate symptoms of AUD. These findings position DHM as a promising candidate for early-onset AD and related dementias and offer potential avenues for addressing alcohol-induced complications like fetal alcohol syndrome and liver failure.

[0050] Advancing DHM into a marketable therapeutic agent poses certain challenges due to its natural composition. One limitation is that DHM itself cannot be patented because it is a natural compound. Additionally, DHM, being a natural flavonoid, has several therapeutic limitations including poor bioavailability and susceptibility to degradation and oxidation upon exposure to air, light, and high temperatures, as well as low solubility, all of which negatively impact its efficacy and ability to be formulated as a therapeutic composition.

[0051] Environmental factors such as pH, temperature, and metal ions influence DHM's stability. Studies indicate that DHM remains stable under weakly acidic conditions with a pH value of < 4. Higher pH levels accelerate its oxidation rate and may lead to irreversible oxidation. To address these challenges, we have utilized principles of molecular splicing to create new compounds based on DHM's core structure, which have shown promising results. While various methods, including chemical, microbial, physical, and enzymatic approaches, were employed to modify DHM's structure, chemical methods are preferred for their simplicity, controllability, and cost-effectiveness.

[0052] Our chemical modifications of DHM focus on a few key strategies. Esterification reactions enhance DHM's fat solubility and antioxidant activity, thereby further enhancing its biological activity. Acylation reactions improve DHM's fat solubility, bacteriostatic, and antioxidant properties. Chelation reactions connect metal ions to DHM, enhancing its antioxidant capabilities. Glycosylation reactions enhance DHM's stability and water solubility. By employing these strategies, the limitations associated with DHM itself can be overcome, paving the way for the development of novel compounds with improved properties for therapeutic applications.

[0053] We have identified that DHM is a candidate for development as a therapeutic agent for neurodegenerative diseases, such as ADRD, neuro-development deficit, such as autism, epilepsy, and alcohol induced complications. Our primary approaches in developing new compounds related to DHM are to maintain its original features while improving its efficacy, enhancing its bioavailability, stability, and manufacturability, and to provide a composition that will achieve enhanced patient compliance.

[0054] We pioneered the synthesis of new DHM compounds by utilizing various synthetic methods to modify the alpha-carbonyl hydroxyl group of DHM. The resulting new DHM compounds exhibit varying degrees of dissociation, resulting in increased buffering capacity across environmental pH values. This innovative approach aims to address DHM's poor bioavailability and stability issues.

[0055] We have developed two series of DHM analogs: phosphorylated DHM, called apDHMs, and a- amine substituted DHM, called aA-DHMs. To keep DHM’s original properties without introducing negative effects, we focused on modifying at the a-position of the ketone. The reasons are:

[0056] 1) The reaction conditions are mild, and the yield of the coupling reactions ranges from moderate to good. Therefore, it is feasible to make the final product in laboratory.

[0057] 2) The a position of the ketone is easily modified with high chemical selectivity.

[0058] 3) The modification on this site conserves the H-acceptor ketone; thus, it won’t compromise the favorable bioactivity of the original compound.

[0059] 4) The modification we made have enhanced interaction with the targeting protein with the introduction of the amphoteric chain. For example: i) Phosphorylation is an organic process that adds a phosphate group to a compound. This process is crucial in biochemistry and molecular biology, playing a key role in many areas, including protein and enzyme activity, sugar metabolism, energy storage and release, and the cellular transfer of free energy. In biological systems, phosphorylation involves adding a phosphoryl (PO3) group to a molecule, which is essential for cellular energy storage and transfer. ii) An amino group is a functional group consisting of a nitrogen atom bonded to two hydrogen atoms. Adding an amino group to an organic compound forms an amine. Biogenic amines are low- molecular-weight organic bases that are formed and degraded as part of normal metabolism. These biogenic amines play several physiological roles in humans, such as aiding gut digestive enzymes and microbes, which are crucial in regulating intestinal functions, including digestion, absorption, and local immunity. iii) Amines, organic compounds featuring a nitrogen atom bonded to alkyl or aryl groups, serve as a foundation for this process. By leveraging the properties of amines, we can effectively regulate the release of the new active DHM compounds in response to different pH environments, thereby enhancing bioavailability.

[0060] We utilized various amines to replace the alpha-carbonyl hydroxyl group of DHM, resulting in the formation of DHM-amme or -ammonium compounds, each exhibiting distinct degrees of dissociation.

[0061] Our DHM salts have high and controllable dissociation rates. These DHM salts possess enhanced buffering capacity across physiological pH values, thereby addressing the challenges of poor bioavailability and stability associated with DHM. Furthermore, this approach enables controlled release of a compound with effective DHM-like properties, offering improved efficacy and usability.

[0062] The modifications described above impart the physicochemical properties of phosphoryl and amine groups. The introduction of these two groups improve solubility, bioavailability, and keep DHM’s favorable properties without introducing negative effects.

[0063] Definitions.

[0064] The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley ’s Condensed Chemical Dictionary 14thEdition, by R.J. Lewis, John Wiley & Sons, New York, N.Y., 2001.

[0065] References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Further, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.

[0066] The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations.

[0067] The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrases "one or more" and "at least one" are readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit. For example, one or more substituents on a phenyl nng refers to one to five, or one to four, for example if the phenyl ring is disubstituted.

[0068] As will be understood by the skilled artisan, all numbers, including those expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value without the modifier "about" also forms a further aspect

[0069] The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph.

[0070] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. It is therefore understood that each unit between two particular units are also disclosed. For example, if 10 to 15 is disclosed, then 11, 12, 13, and 14 are also disclosed, individually, and as part of a range. A recited range (e.g., weight percentages or carbon groups) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

[0071] This disclosure provides ranges, limits, and deviations to variables such as volume, mass, percentages, ratios, etc. It is understood by an ordinary person skilled in the art that a range, such as “numberl” to “number2”, implies a continuous range of numbers that includes the whole numbers and fractional numbers. For example, 1 to 10 means 1, 2, 3, 4, 5, ... 9, 10. It also means 1.0, 1.1, 1.2. 1.3, ... , 9.8, 9.9, 10.0, and also means 1.01, 1.02, 1.03, and so on. If the variable disclosed is a number less than “numberlO”, it implies a continuous range that includes whole numbers and fractional numbers less than numberlO, as discussed above. Similarly, if the variable disclosed is a number greater than “numberlO”, it implies a continuous range that includes whole numbers and fractional numbers greater than numberlO. These ranges can be modified by the term “about”, whose meaning has been described above.

[0072] The recitation of a), b), c), ... or i), ii), iii), or the like in a list of components or steps do not confer any particular order unless explicitly stated.

[0073] One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.

[0074] The term "contacting" refers to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e g., in a solution, in a reaction mixture, in vitro, or in vivo.

[0075] An "effective amount" refers to an amount effective to treat a disease, disorder, and / or condition, or to bring about a recited effect. For example, an effective amount can be an amount effective to reduce the progression or severity of the condition or symptoms being treated. Determination of a therapeutically effective amount is well within the capacity of persons skilled in the art. The term "effective amount" is intended to include an amount of a compound described herein, or an amount of a combination of compounds described herein, e.g., that is effective to treat or prevent a disease or disorder, or to treat the symptoms of the disease or disorder, in a host. Thus, an "effective amount" generally means an amount that provides the desired effect.

[0076] Alternatively, the terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate "effective" amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient's age, size, type or extent of disease, stage of the disease, route of administration of the compositions, the type or extent of supplemental therapy used, ongoing disease process and type of treatment desired (e.g., aggressive vs. conventional treatment).

[0077] The terms "treating", "treat" and "treatment" include (i) preventing a disease, pathologic or medical condition from occurring (e.g., prophylaxis); (ii) inhibiting the disease, pathologic or medical condition or arresting its development; (iii) relieving the disease, pathologic or medical condition; and / or (iv) diminishing symptoms associated with the disease, pathologic or medical condition. Thus, the terms "treat", "treatment", and "treating" can extend to prophylaxis and can include prevent, prevention, preventing, lowering, stopping or reversing the progression or severity of the condition or symptoms being treated. As such, the term "treatment" can include medical, therapeutic, and / or prophylactic administration, as appropriate.

[0078] As used herein, "subject" or “patient” means an individual having symptoms of, or at risk for, a disease or other malignancy. A patient may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, the patient may include either adults or juveniles (e.g., children). Moreover, patient may mean any living organism, preferably a mammal (e.g., human or non-human) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods provided herein, the mammal is a human.

[0079] As used herein, the terms “providing”, “administering,” “introducing,” are used interchangeably herein and refer to the placement of a compound of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compound can be administered by any appropriate route that results in delivery to a desired location in the subject.

[0080] The compound and compositions described herein may be administered with additional compositions to prolong stability and activity of the compositions, or in combination with other therapeutic drugs.

[0081] The terms "inhibit", "inhibiting", and "inhibition" refer to the slowing, halting, or reversing the growth or progression of a disease, infection, condition, or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth or progression that occurs in the absence of the treatment or contacting.

[0082] The term “substantially” as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.

[0083] Wherever the term “comprising” is used herein, options are contemplated wherein the terms “consisting of’ or “consisting essentially of’ are used instead. As used herein, “comprising” is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of' excludes any element, step, or ingredient not specified in the aspect element. As used herein, "consisting essentially of' does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect. In each instance herein any of the terms "comprising", "consisting essentially of' and "consisting of' may be replaced with either of the other two terms. The disclosure illustratively described herein may be suitably practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0084] This disclosure provides methods of making the compounds and compositions of the invention. The compounds and compositions can be prepared by any of the applicable techniques described herein, optionally in combination with standard techniques of organic synthesis. Many techniques such as etherification and esterification are well known in the art. However, many of these techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6; as well as standard organic reference texts such as March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Ed., by M. B. Smith and J. March (John Wiley & Sons, New York, 2001); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modem Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (Pergamon Press, New York, 1993 printing); Advanced Organic Chemistry, Part B: Reactions and Synthesis, Second Edition, Cary and Sundberg (1983); for heterocyclic synthesis see Hermanson, Greg T., Bioconjugate Techniques, Third Edition, Academic Press, 2013.

[0085] The formulas and compounds described herein can be modified using protecting groups. Suitable amino and carboxy protecting groups are known to those skilled in the art (see for example, Protecting Groups in Organic Synthesis, Second Edition, Greene, T. W., and Wuts, P. G. M., John Wiley & Sons, New York, and references cited therein; Philip J. Kocienski; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), and references cited therein); and Comprehensive Organic Transformations, Larock, R. C ., Second Edition, John Wiley & Sons, New York (1999), and referenced cited therein.

[0086] The term "halo" or "halide" refers to fluoro, chloro, bromo, or iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0087] The term "alkyl" refers to a branched or unbranched hydrocarbon having, for example, from 1- 20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbon atoms; or for example, a range between

[0088] 1-20 carbon atoms, such as 2-6, 3-6, 2-8, or 3-8 carbon atoms. As used herein, the term “alkyl” also encompasses a “cycloalkyl”, defined below. Examples include, but are not limited to, methyl, ethyl, 1- propyl, 2-propyl (Ao-propyl), 1-butyl, 2-methyl-l-propyl isobutyl), 2-butyl (sec-butyl), 2-methyl-2- propyl ( / -butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3 -methyl- 1-butyl, 2- methyl- 1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3- methyl-3 -pentyl, 2-methyl-3 -pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted, for example, with a substituent described below or otherwise described herein. The alkyl can also be optionally partially or fully unsaturated. As such, the recitation of an alkyl group can include an alkenyl group or an alkynyl group. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).

[0089] An alkylene is an alkyl group having two free valences at a carbon atom or two different carbon atoms of a carbon chain. Similarly, alkenylene and alkynylene are respectively an alkene and an alkyne having two free valences at two different carbon atoms, or an alkenylene can have the two free valences on the same carbon.

[0090] The term "cycloalkyl" refers to cyclic alkyl groups of, for example, from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1 - cyclopent- 1-enyl, 1 -cyclopent-2-enyl, 1-cy clopent-3 -enyl, cyclohexyl, 1 -cyclohex- 1-enyl, 1-cyclohex-

[0091] 2-enyl, l-cyclohex-3-enyl, and the like.

[0092] The term “heteroatom” refers to any atom in the periodic table that is not carbon or hydrogen. Typically, a heteroatom is O, S, N, P. The heteroatom may also be a halogen, metal or metalloid.

[0093] The term "heterocycloalkyl" or “heterocyclyl” refers to a saturated or partially saturated monocyclic, bicyclic, or polycyclic ring containing at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3- to 10-membered, more preferably 4 to 7 membered. Examples of suitable heterocycloalkyl substituents include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, 1,3-diazapanyl, 1 ,4-diazapanyl, 1,4-oxazepanyl, and 1,4-oxathiapanyl. The group may be a terminal group or a bridging group.

[0094] The term "aryl" refers to an aromatic hydrocarbon group derived from the removal of at least one hydrogen atom from a single carbon atom of a parent aromatic ring system. The radical attachment site can be at a saturated or unsaturated carbon atom of the parent ring system. The aryl group can have from 6 to 30 carbon atoms, for example, about 6-10 carbon atoms. The aryl group can have a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. The aryl can be unsubstituted or optionally substituted with a substituent described below. For example, a phenyl moiety or group may be substituted with one or more substituents Rxwhere Rxis at the ortho-, meta-, or para-position, and X is an integer variable of 1 to 5.

[0095] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. The heteroaryl can be unsubstituted or substituted, for example, with one or more, and in particular one to three, substituents, as described in the definition of "substituted". Typical heteroaryl groups contain 2-20 carbon atoms in the ring skeleton in addition to the one or more heteroatoms, wherein the ring skeleton comprises a 5-membered ring, a 6-membered ring, two 5-membered rings, two 6-membered rings, or a 5-membered ring fused to a 6-membered ring. Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl, P-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridmyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O, alkyl, aryl, or (Ci-C6)alkylaryl. In some embodiments, heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benzo-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.

[0096] As used herein, the term "substituted" or “substituent” is intended to indicate that one or more (for example, in various embodiments, 1-10; in other embodiments, 1-6; in some embodiments 1, 2, 3, 4, or 5; in certain embodiments, 1, 2, or 3; and in other embodiments, 1 or 2) hydrogens on the group indicated in the expression using “substituted” (or “substituent”) is replaced with a moiety selected from the indicated group(s), or with a suitable group known to those of skill in the art, such as a substituent moiety recited below, provided that the indicated atom’s normal valency is not exceeded and that the substitution results in a stable compound. Suitable substituent moieties and indicated groups include, e.g., alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkanoyl, alkoxy carbonyl, amino, alkylamino, dialkylamino, carboxyalkyl, alkylthio, alkylsulfinyl, and alkylsulfonyl. Substituents of the indicated groups can be those recited in a specific list of substituents described herein, or as one of skill in the art would recognize, can be one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethylthio, difluoromethyl, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, and cyano. Suitable substituents of indicated groups can be bonded to a substituted carbon atom include F, Cl, Br, I, OR', 0C(0)N(R')2, CN, CF3, OCF3, R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', SO2R', SO2N(R')2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, C(S)N(R')2, (CH2)O-2NHC(0) , N(R')N(R,)C(O)R, N(R)N(R')C(O)OR, N(R')N(R')CON(R')2, N(R')SO2R', N(R')SO2N(R')2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')2, N(R')C(S)N(R')2, N(COR')COR', N(OR')R, C(=NH)N(R')2, C(O)N(OR')R, or C(=NOR')R’ wherein R’ can be hydrogen or a carbon-based moiety (e.g., (Ci-Ce)alkyl), and wherein the carbon-based moiety can itself be further substituted. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. When a substituent is divalent, such as O, it is bonded to the atom it is substituting by a double bond; for example, a carbon atom substituted with O forms a carbonyl group, C=O.

[0097] Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, which form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane- polarized light. In describing an optically active compound, the prefixes D and L, or R and S. are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0098] Stated Embodiments of the Technology.

[0099] 1. A compound of Formula I: wherein

[0100] A is a direct bond, NH, O, -OP(=O)(OH)O-, or -(OCFbCE^pO- wherein p is 1, 2, or 3; each R1is independently -(Ci-Cg)alkyl, -(C3-C6)cycloalkyl, -(C=O)(Ci-C6)alkyl, or H;

[0101] R2is -(Ci-Cg)alkyl, -(C3-C6)cycloalkyl, -(C=O)(Ci-C6)alkyl, or H;

[0102] R3is H, -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, or -(C=O)(Ci-C6)alkyl;

[0103] R4is nitrogen heterocycle, amino, guanidine, amino acid, or saccharide, each optionally substituted; or when A is NH, O, -OP(=O)(OH)O-, or -(OCH2CH2)PO- R4is optionally H; and m is 1, 2, 3, 4, 5, 6, 7, or 8, wherein one or more carbon atoms of the moiety (CH2)mis optionally substituted with unbranched or branched -(Ci-C6)alkyl, and / or the moiety is optionally interrupted with O or NH; or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, A is a direct bond. In some embodiments, A is NH or O. In some embodiments, A is -OP(=O)(OH)O- In some embodiments, A is -(OCH2CH2)PO- wherein p is 1, 2, or 3. In some embodiments, each R1is independently -(Ci-C6)alkyl. In some embodiments, R2is -(Ci- C6)alkyl. In some embodiments, R2is H. In some embodiments, R4is nitrogen heterocycle or amino.

[0105] 2. The compound of embodiment 1, wherein each R1is independently methyl, ethyl, or acetyl.

[0106] 3. The compound of embodiment 1 or 2, wherein R2is methyl, ethyl or acetyl.

[0107] 4. The compound of any one of embodiments 1-3, wherein R3is H.

[0108] 5. The compound of any one of embodiments 1-4, wherein R4is piperidine, piperazine, pyrrolidine, morpholine, alkylamine, aziridine, azetidme, hexose, or pentose; each optionally substituted. In some embodiments, R4is NH2, mono-alkylamine, or dialkylamine. In some embodiments, R4is piperidine, pyrrolidine, morpholine, or aziridine.

[0109] 6. The compound of any one of embodiments 1-5, wherein m is 2, 3, 4, or 5. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. 7. The compound of any one of embodiments 1-6, wherein R4is piperidin-4-yl, N- methylpiperidin-4-yl, A, A-dimethylamine, A-ethylamine, A-isobutylamine, A, A-di ethyl amine. N- methyl-A-ethylamme, pyrrolidm-l-yl, A-methyl-pyrrolidin-3-yl, or hydroxy-pyrrolidm-l-yl.

[0110] 8. The compound of any one of embodiments 1-7, represented by Formula IIA or Formula IIB: wherein

[0111] R4is amino, piperidine, piperazine, pyrrolidine, morpholine, guanidine, aziridine, or azetidine, each optionally substituted; and m is 3 or 4; or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compounds is represented by Formula IIA. In some embodiments, the compounds is represented by Formula IIB. In some embodiments, R4is amino, piperidine, pyrrolidine, guanidine, aziridine, or azetidine.

[0113] 9. The compound of any one of embodiments 1-7, represented by Formula IIC or Formula IID: wherein

[0114] R4is amino, piperidine, piperazine, pyrrolidine, morpholine, guanidine, aziridine, or azetidine, each optionally substituted, for example with -(Ci-Ce)alkyl; and m is 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof

[0115] In some embodiments, the compounds is represented by Formula IIC. In some embodiments, the compounds is represented by Formula IID. In some embodiments, R4is amino, piperidine, pyrrolidine, guanidine, aziridine, or azetidine.

[0116] 10. The compound of any one of embodiments 1-7, represented by Formula IIIA, IIIB, or IIIC: wherein

[0117] R5is H or -(Ci-C6)alkyl;

[0118] R6is H, C-NR7(N(R7)2), or -(Ci-C6)alkyl; and each R7is independently H or -(Ci-Ce)alkyl; or

[0119] R5and R6taken together with the nitrogen atom to which they are attached form a 3- membered, 4-membered, 5-membered, or 6-membered nitrogen heterocycle; or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the compounds is represented by Formula IIIA. In some embodiments, the compounds is represented by Formula IIIB. In some embodiments, the compounds is represented by Formula IIIC. In some embodiments, R5is H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R6is H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R6is -C=NR7(N(R7)2). In some embodiments, R7is H, methyl, ethyl, propyl, or isopropyl. In some embodiments, R5and R6taken together with the nitrogen atom to which they are attached form a 3- membered or 5 -membered nitrogen heterocycle. In some embodiments, R5and R6taken together with the nitrogen atom to which they are attached form a 6-membered nitrogen heterocycle.

[0121] 11. The compound of embodiment 10, wherein R5and R6taken together with the nitrogen atom to which they are attached form pyrrolidm-l-yl or hydroxyl-substituted pyrrolidm-l-yl.

[0122] 12. The compound of any one of embodiments 1-11, wherein each -(Ci-Ce)alkyl is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or hexyl.

[0123] 13. The compound of any one of embodiments 1-12, wherein the substituents at the 2-position and at the 3 -position of the chromanone ring of Formulas I, IIA-D, or IIIA-C have a / ran.s -configuration.

[0124] 14. The compound of any one of embodiments 1-13, wherein the compound is: or a pharmaceutically acceptable salt thereof. 15. A composition comprising a compound of any one of embodiments 1-14 and an excipient, one or more natural products, or both an excipient and one or more natural products.

[0125] 16. The composition of embodiment 15, wherein composition comprises one or more natural products selected from ashwagandha extract, valerian extract, magnolia extract jujube extract, lemon balm, L-theanine, melatonin, folic acid, and vitamin B. In some embodiments, the composition comprises ashwagandha extract. In some embodiments, the composition comprises valerian extract. In some embodiments, the composition comprises magnolia extract.

[0126] 17. A method for treating a subject in need of neuromodulation comprising: administering to the subject an effective amount of the compound or composition according to any one of embodiments 1-16 to provide the neuromodulation; wherein optionally the neuromodulation effectively aids the treatment of Alzheimer’s disease related dementia (ADRD) , including Alzheimer’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, as well as neurodegenerative diseases including Parkinson’s disease and Huntington’s disease or a combination thereof. In some embodiments, the neuromodulation effectively aids the treatment of Alzheimer’s disease. 18. The method of embodiment 17, wherein the neuromodulation effectively aids a pathological change in the subject, and the pathological changes comprises increased A0 and Tau, neuroinflammation, cognitive deficit, memory deficit, or a combination thereof.

[0127] 19. The method of embodiment 17 or 18, wherein the neuromodulation effectively aids insomnia, sleep, a sleep disorder, anxiety, depression, aggression, cognition, memory, or a combination thereof. In some embodiments, the neuromodulation effectively aids insomnia or anxiety.

[0128] 20. The method of any one of embodiments 17-19, wherein the neuromodulation effectively aids the treatment of post-traumatic stress disorder, autism, alcohol use disorder, fetal alcohol syndrome, addiction, cancer, or a combination thereof. In some embodiments, the neuromodulation effectively aids the treatment of alcohol use disorder.

[0129] 21. The method of any one of embodiments 16-20 wherein the effective amount administered is an oral dose of about 0.5 grams to about 3 grams of the composition.

[0130] 22. The method of any one of embodiments 16-21, wherein the effective amount administered is about 0.1 grams, about 0.5 grams, about 1 gram, about 1.5 grams, about 2 grams, about 2.5 grams, about 3.0 grams, about 3.5 grams, about 4 grams, or any amount between the recited amounts.

[0131] 23. The compound, composition, or method of any one embodiments 1 -22, wherein the compound is: 5-hydroxy-7-methoxy-3-(4-(l-methylpiperidin-4-yl)butyl)-2-(3,4,5-trimethoxyphenyl)chroman-4-one; 3-(3-(dimethylamino)propyl)-5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chroman-4-one;

[0132] 3-(3-(ethyl(methyl)amino)propyl)-5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chroman-4-one; 3-(3-(diethylamino)propyl)-5-hydroxy-7-methoxy-2-(3,4,5-trimethoxyphenyl)chroman-4-one; l-(3-(5-hydroxy-7-methoxy-4-oxo-2-(3,4,5-trimethoxyphenyl)chroman-3-yl)propyl)guanidine; 5-hydroxy-7-methoxy-3-(3-(pyrrolidin-l-yl)propyl)-2-(3,4,5-trimethoxyphenyl)chroman-4-one;

[0133] 5-hydroxy-3-(3-(3-hydroxypyrrolidin-l-yl)propyl)-7-methoxy-2-(3,4,5-trimethoxyphenyl)chroman-4- one;

[0134] 5-hydroxy-7-methoxy-3-(3-(l-methylpyrrolidin-3-yl)propyl)-2-(3,4,5-trimethoxyphenyl)chroman-4- one;

[0135] (2R,3R)-3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one;

[0136] (2R,3S)-3-(ethylamino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one;

[0137] (2R,3S)-3-((3-aminopropyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one; (2R,3S)-3-((4-aminobutyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one;

[0138] (2R,3S)-3-((5-aminopentyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one; (2R,3S)-3-((2-(dimethylamino)ethyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one;

[0139] (2R,3S)-3-((3-(dimethylamino)propyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4- one;

[0140] (2R,3S)-3-((2-(aziridin-l-yl)ethyl)amino)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-4-one; (2R,3S)-5,7-dihydroxy-3-((2-(pyrrolidin-l-yl)ethyl)amino)-2-(3,4,5-trihydroxyphenyl)chroman-4-one; (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl methyl hydrogen phosphate; (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-tnhydroxyphenyl)chroman-3-yl ethyl hydrogen phosphate;

[0141] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl ((methylamino)methyl) hydrogen phosphate;

[0142] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl isobutyl hydrogen phosphate;

[0143] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl ((dimethylamino)methyl) hydrogen phosphate; aziridin-l-ylmethyl ((2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl) hydrogen phosphate;

[0144] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl ((ethylamino)methyl) hydrogen phosphate;

[0145] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl ((isobutylamino)methyl) hydrogen phosphate;

[0146] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl (3-(dimethylamino)propyl) hydrogen phosphate; or

[0147] (2R,3R)-5,7-dihydroxy-4-oxo-2-(3,4,5-tnhydroxyphenyl)chroman-3-yl (3-(pyrrolidin-l-yl)propyl) hydrogen phosphate; or a pharmaceutically acceptable salt thereof, such as an amine salt or amino acid salt thereof.

[0148] Further Aspects of the Technology.

[0149] This disclosure provides a method of treating a disease or disorder of the immune-system and glutamate-system / GABA-system imbalance, or symptoms thereof in a subject which comprises administering an analog of DHM, or a metabolite of DHM-analog to the subject.

[0150] In some aspects, the disease or disorder is Alzheimer's disease, neuron damage, or seizures, and any neuro-system development delay, such as Autism. In other aspects, the subject: is afflicted with Alzheimer's disease, is diagnosed as having Alzheimer's disease, is at risk of having Alzheimer's disease, has recurrent seizures, is diagnosed with having epilepsy, is likely to have one or more seizures, has or is likely to have excessive glutamate levels and / or excessive calcium influx.

[0151] In some aspects, the symptom is cognitive function decline, increased anxiety, or one or more convulsions caused by a seizure. In other aspects, the decreased cognitive function is a deficit in recognition, learning, and / or memory by the subject as compared to a control.

[0152] Additionally, this disclosure provides a method of treating, inhibiting, and / or reducing abnormally high levels of amyloid-P (A0) peptides in a subject which comprises administering an analog of DHM, or a metabolite of DHM-analog to the subject. Furthermore, this disclosure provides a method of reducing glutamate-mediated excitotoxicity- induced neuron loss and / or damage in a subject which comprises administering an analog of DHM, or a metabolite of DHM-analog to the subject.

[0153] In various aspects of the technology, the analog of DHM, or the metabolite of DHM-analog is orally administered. In various other aspects of the technology, the analog of DHM, or the metabolite of DHM is chronically administered. In yet other aspects of the technology, more than one dose of the analog of DHM, or the metabolite of DHM-analog is administered to the subject over a period of the about three months or more.

[0154] In some aspects of the technology, the analog of DHM, or the metabolite of DHM-analog is administered in a therapeutically effective amount. In other aspects of the technology, the therapeutically effective amount is about 0.001-2000 mg / kg, preferably about 0.01-1000 mg / kg, preferably about 0.1-100 mg / kg, more preferably about 0.1-10 mg / kg, and most preferably about 0.1-5 mg / kg of the subject. In some other aspects of the technology, the analog of DHM, or the metabolite of DHM-analog is administered daily. In additional aspects of the technology, the subject is a mammal, preferably a human.

[0155] In various aspects of the technology, the methods further comprise administering to the subject an analog of DHM, or a metabolite of DHM-analog selected from the group consisting of anti-epileptic compounds, anticonvulsants, and compounds known to ameliorate one or more symptoms of Alzheimer's disease and related dementias, and any disorders of inhibitory neuro-system development.

[0156] This disclosure also provides the use of an analog of DHM, or a metabolite of DHM-analog to treat a disease or disorder of the glutamatergic system, e.g., Alzheimer's disease and related dementias (ADRD), neuron damage, and any disorders of inhibitory neuro-system development, and / or loss, and seizures, or a symptom thereof in a subject.

[0157] In some aspects of the technology, a medicament, a foodstuff, or a food additive for the treatment of a disease or disorder of the glutamatergic system, e.g., ADRD, neuron damage and / or loss, and seizures, or a symptom thereof which comprises an analog of DHM, or a metabolite of DHM- analog is administered in an amount of about 10-2000 mg.

[0158] In some other aspects of the technology, a medicament, a foodstuff, or a food additive for the treatment of a disease or disorder of the glutamatergic system, e.g., ADRD, neuron damage and / or loss, and seizures, or a symptom thereof which comprises dihydromyricetin (DHM), an analog of DHM, or a metabolite of DHM is administered in an amount of about 10-2000 mg to be orally administered daily.

[0159] In some aspects of the technology, treatment with an analog of DHM, or a metabolite of DHM- analog abolishes single dose EtOH intoxication-induced tolerance to EtOH itself. In some other aspects of the technology, administration of an analog of DHM, or a metabolite of DHM-analog antagonizes alcohol intoxication-induced GABAAR plasticity. In yet other aspects of the technology, an analog of DHM, or a metabolite of DHM-analog is administered after alcohol exposure and withdrawal. In some other aspects of the technology, treatment with an analog of DHM is useful for anxiety, depression, sleep disorder, or a combination thereof. In some other aspects of the technology, treatment with an analog of DHM is useful for Alcohol Use Disorder (AUD), Fetal Alcohol Syndrome (FAS), Alcohol Liver Disease.

[0160] Uses of DHM and DHM-based Compounds.

[0161] Alcoholism. PCT / USPTO13 / 520,727 (2011) is incorporated herein by reference: Methods Of Treating Alcohol Intoxication, Alcohol Use Disorders And Alcohol Abuse Which Comprises The Administration Of Dihydromyricetin). Chronic alcohol consumption not only leads to primary and secondary aggravated alcoholic liver disease but also correlates with impaired liver function and increased mortality. The early stage of alcoholic liver disease includes fatty liver, which is usually reversible. While the last stage of alcohol-intoxication induced liver dysfunction is hepatic encephalopathy (HE), which is irreversible due to lack of effective medication. Therefore, counteracting the progress of liver damage and preventing liver dysfunctions induced by heavy drinking can prevent HE.

[0162] In industrialized countries, about 60-70% of populations above the age of 18 years consume alcohol. All over Europe, more than 45 million individuals display signs of alcohol-related organ damage, of which alcoholic liver disease comprises the largest group accounting for approximately 50% of all chronic liver diseases. Taken together, in Europe and the United States advanced alcoholic liver damage is responsible for more than 50000 annual deaths due to alcoholic liver cirrhosis and associated complications. Over 90% of heavy drinkers have liver damage, such as fatty liver, and some of these individuals progress to more severe liver damage, such as alcoholic cirrhosis, a condition that often precedes HE. For individuals with mild to moderate alcoholic hepatitis, the main therapeutic is to remove alcohol. For alcoholic hepatitis and cirrhosis with clinical signs, the therapeutic treatment includes psychotherapy, social support, nutritional supplementation and, increasingly, pharmaceuticals that may counteract some of the pathogenic events in alcoholic liver disease. A number of treatment options have been used in the population of alcohol-intoxication induced liver dysfunction, but with varying degrees of success.

[0163] The most common symptoms of earlier stage of HE is associated with cognitive and motor abnormalities. In healthy subjects, nitrogen-containing compounds from the intestine, generated by gut bacteria from food, are transported by the portal vein to the liver, where 80-90% is metabolized through the urea cycle and / or excreted immediately. This process is impaired in all subtypes of HE. Nitrogenous waste products accumulate in the systemic circulation. The most important waste product is ammonia (NH3). This small molecule crosses the blood brain barrier and is absorbed and metabolized by the Astrocytes, a population of cells in the brain. Astrocytes use ammonia when synthesizing glutamine from glutamate. The increased levels of glutamine lead to cytotoxic or neurotoxicity, as the results, brain becomes edema and appearing cognitive and motor abnormalities. The medications for alleviating both cognitive and motor abnormalities are lacking.

[0164] Administration of DHM reduces the serum alcohol concentration in mice. DHM has an anti- anxiety effect induced by alcohol and DHM attenuates locomotor activity retard in HE-like behaviors induced by alcohol. DHM also reduces the duration of LORR. Furthermore, DHM improves the change of hepatic pathology and has a hepatoprotective function.

[0165] Neurodegenerative diseases and neurodevelopment disorders. Alzheimer’s disease and related dementias (ADRD) are the leading progressive neurodegenerative disorders characterized by a decline in cognition, memory, and learning abilities, psychiatric disorders, pathologically irreversible loss of synapses in specific brain regions, and extracellular amyloid plaques. Presently, there is no cure for the disease, which worsens as it progresses and eventually leads to death [3-6], Currently, the USA Food and Drug Administration (FDA) has approved five medications and two antibodies targeting amyloidbeta (A0) for the treatment of Alzheimer’s disease. These approved pharmacotherapies include acetylcholinesterase (AChE) inhibitors tacrine, rivastigmine, galantamine, and donepezil. These drugs do not cure Alzheimer’s disease but temporarily ameliorate symptoms of cognition and memory. The other approved drug, memantine, is believed to help treat Alzheimer’s disease by interfering with or reducing the effects of N-methyl-D-aspartate (NMD A) receptors, a major excitatory protein found in the bram. Unfortunately, none of these drugs is curative, and these pharmacotherapies have only modest positive therapeutic effects on memory loss in Alzheimer’s patients. Moreover, the use of these drugs can also have unwanted side effects that limit their utility. For example, a systematic review of evaluations of memantine's efficacy and safety indicates that it does not improve cognition or leaming / memory function among patients with mild cognitive impairment and is associated with a greater risk of gastrointestinal harm.

[0166] Alzheimer's disease (AD) is the leading cause of dementia, presenting a significant unmet medical need worldwide. The pathogenesis of AD involves various pathophysiological events, including the accumulation of amyloid and tau, neuro-inflammation, and neuronal injury. Clinical tnals focusing on new drugs for AD were documented in 2020, and subsequent developments have emerged since then. Notably, the US-FDA has approved Lecanemab and donanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. The two antibody drugs reduce the accumulation of amyloid plaques and slow down the decline of cognition but do not improve cognition and memory. These drugs do not revers nor stop the progression of the disease. These drugs have known site effects such as infusion site reaction, which can cause pain or swelling.

[0167] To this end, our laboratory has reported that dihydromyricetin (DHM), a plant flavonoid purified from Hovenia or teas that acts as a positive allosteric modulator of GABAARS, can significantly improve cognitive and learning abilities as determined using a transgenic mouse model of Alzheimer’s disease. Refer to "Dihydromyricetin ameliorates behavioral deficits and reverses neuropathology of transgenic mouse models of Alzheimer’s disease" (Figure 3).

[0168] Moreover, we showed that DHM reverses the neuropathology of Alzheimer’s disease in this model. Mechanistically, we found that the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal slices from transgenic Alzheimer’s disease mice were significantly lower. We have named this phenomenon “silent inhibitory synapses” because of the properties we measured compared with control animals. We also found that gephyrin, a postsynaptic GABAAR anchor protein that regulates the formation and plasticity of GABAergic synapses, was reduced to less than 50% in the hippocampus and cortex of Alzheimer’s disease animals compared to control wild-type animals. Interestingly, there were no significant differences in the GABAAR subunit levels between Alzheimer’s disease and control animals. Notably, we found that oral administration of DHM for 3 months restored gephyrin levels in a dose-dependent manner and restored GABAergic transmission as well as functional synapses in our transgenic mouse model of Alzheimer’s disease. In addition, DHM treatment reduced amyloid-P (AP) peptides in the brains of these animals. Importantly, the pathological recovery resulting from DHM treatment paralleled improvements in cognition and learning (Figure 3).

[0169] Anxiety (Figure 4 and Figure 5). We investigated the pharmacological mechanisms of DHM on anxiety-like behavior and its effects in the CNS to better understand its anxiolytic activity. We studied its effects in socially isolated C57BL / 6J mice that demonstrated (a) increased anxiety-like behavior; (b) impaired postsynaptic and extrasynaptic GABAAR-mediated neurotransmission and (c) reduced hippocampal gephyrin levels. Using these mouse models of anxiety, we found that these impairments were reversed by DHM administration. These results suggest that social deprivation contributes to anxiety. The anxiolytic properties of DHM are consistent with our previous findings of the anxiolytic properties of DHM on aged transgenic Alzheimer’s disease mice.

[0170] From our studies, we found that DHM reversed the anxiety-like behavior in socially isolated mice as measured by an elevated plus maze activity in the open / closed arms (Figure 4), locomotory, and exploratory behaviors (data not shown). Furthermore, biochemical analyses of the ATP levels and gephyrin protein expression in the hippocampi of mice treated with DHM were found to be maintained relative to socially isolated mice without treatment or with treatment of diazepam (Figure 5). Our data indicate that DHM reverses the anxiety-like behavior induced by socially isolation and provides a biochemical means of maintaining ATP concentrations that are otherwise reduced in anxious mice. Collectively, these results suggest anxiolytic activity of DHM may provide benefits for the treatment of anxiety-like disorders and potential cognitive disorders. Due to the need of safe and effective anxiolytics, the advancement of DHM as a candidate would provide a stable and cost-effective therapeutic option for the treatment of anxiety disorders.

[0171] Liver Diseases (Figure 6-8). Among the causes of chronic liver disease (CLD), alcohol-related liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most important contributors to the global burden of disease. The global prevalence of NAFLD in adults is estimated to be approximately 25% of the total population. 67% of overweight individuals and 94% of obese individuals reported to have NAFLD. NAFLD rates dramatically increase with the increasing rates of obesity and are also impacted by exposure to hepatoxms in the environment, such as alcohol, acetaminophen, and carbon tetrachloride (CCL4). Due to the essential function of the liver in metabolism and detoxification, injuries to the liver need to be rapidly and efficiently remedied.

[0172] Currently, no treatment options are available for CLD, including NAFLD, and it is often suggested that the individual modify their lifestyle as part of a medical program. Due to these rising rates, and lack of treatment options, there is a strong need for the development and advancement of safe and effective candidate therapies for the treatment of NAFLD. To this end, our lab has recently investigated the therapeutic benefits of an active bioflavonoid, dihydromyricetin (DHM), for the treatment of alcohol-mediated liver injury and disease. These studies have illustrated that DHM benefits the fat metabolism in the liver of alcohol (ethanol)-fed mice, resulting in less fatty liver development, reduced liver weights, and triglyceride content.

[0173] Furthermore, other labs investigating the potential of DHM liver protection against liver injury agents, such as CCL4, have found that DHM is effective in reducing the necrosis and apoptosis. Furthermore, DHM showed significant effects on the development of NAFLD and non-alcoholic steatohepatitis (NASH) in mice models, suggesting a potential role in preventing NAFLD in regard to high fat diets and obesity.

[0174] Expanding upon these findings, our lab investigated the effects of DHM on lipid metabolism in vitro and found that DHM reduces lipid metabolism signaling in hepatoblastoma (HB) cell models, HepG2 and VL- 17A, frequently used for understanding pharmacological mechanisms in hepatocytes. As shown in Figure 8, the treatment of DHM at 5 pM results in a reduction of the expression of the mature sterol regulatory element binding protein (SREBP)-l (Figure 8A) and expression of pro- inflammatory cytokines (Figure 8B).

[0175] These results indicate a potential mechanism of DHM on the lipid metabolic pathways, in which we observed reduced lipid accumulation and signaling in the HB cell models. Therefore, DHM may potentially counteract NAFLD via the reduction of lipid metabolic pathways and induction of lipid breakdown.

[0176] Alcoholic liver disorder (ALD) affects over 14 million people in the United States and costs approximately $249 billion each year. Unfortunately, it is becoming more common for younger patients to suffer from ALD, and these rates are expected to continually rise due to increasing incidents of alcohol use disorder (AUD). Although there are currently three FDA-approved medications to pharmacologically treat AUD, none are effective in reducing alcohol consumption and the onset of ALD. Also, accumulating evidence suggests that individuals that regularly consume alcohol must alter their lifestyle, especially if they are at higher risk for developing fatty liver. Unfortunately, patient compliance remains low, and the on-market therapies for AUD are ineffective for treating this behavior.

[0177] Our studies show that Dihydromyncetm (DHM) is a potential therapy for ALD and the subsequent organ damage associated with AUD. Of its reported properties, DHM has been found to act as an antioxidant that can potentially counteract ethanol intoxication, reduce consumption, and protect cells against oxidative stress. To promote the efficacy and safety of DHM as a new therapeutic for the reduction / prevention of ALD and AUD behavior we utilized animal models and in vitro studies to elucidate its mechanisms and potential in the liver. In these models, we gathered valuable insight into the pharmacological benefits of DHM for a disorder with little to no effective treatment options.

[0178] In vivo studies utilizing C57BL / 6J mice, a genetic strain of mice with high alcohol (ethanol / EtOH) preference, and chronic EtOH feeding over a 10-week period found that DHM administration (5 and 10 mg / kg; daily intraperitoneal [i.p.] injection) resulted in a significant reduction in liver lipid accumulation, liver weights, and liver triglycerides (Figure 7).

[0179] Cancer. DHM has been proposed to have anti-cancer benefits. Due to the antioxi dative properties of DHM, it has been found that DHM is capable of inhibiting cancer cell proliferation as evidenced by studies using human hepatoma cells and gastric cancer cells via p-53 mediated pathways. Furthermore, other studies have found that DHM has effective anti-tumor activity against ovarian cancer, breast cancer, liver cancer, colon cancer, and lung cancer. Collectively, DHM is being found to have anti-cancer benefits in cell and animal models.

[0180] To this end, we investigated the effects of DHM on HepG2 and VL-17A hepatoblastoma cell lines. We have found that concentrations of DHM of 50 pM reduce the viability of both HepG2 and VL-17A cells over a 24-hour period (Figure 8). DHM incubation with these cell models also results in the reduction of cell proliferation (data not shown), suggesting anti- cancer effects in these liver hepatoblastoma cell models. Therefore, our data support the anti-cancer properties of DHM in liver hepatobloastoma cell lines.

[0181] Sleep problems (Figure 9). All participants for our sleep study had complained about sleep problems, including couldn’t sleep, hard to fall in sleep, wake up very often 30 mm to 1 hour interval, short sleep time, etc. All participants took one pack / day, containing 150 mg of DHM orally after half hour of dinner (around 7PM). After the next day wake up, participants checked their own sleep time, including dreamed or not, feeling, energy, etc.

[0182] We selected participants with long period of sleep issues (one year to 20 years). Ages were from 30 to 60 years old. After taking one pack of DHM per day without taking other sleep aids for 21 days, the sleep tests were performed on day 0 and day 21. Sleep time (hour) increased from average 5.5 hours to 7.5 hours. After improvement of sleep time is confirmed, we stop the DHM administration and we didn’t see rebound effects. The result suggests that DHM improves the quality of sleep without rebound (Figure 9). Anti-inflammatory / infection: DHM prevents or reduces the damage of air contaminants to the lungs (Figure 10). Experimental: The first three days (Day 1, 2, 3), Mice were divided into 3 groups and were exposed to: (Control A) normal air for 10 minutes. The (Contaminated B) test gas SO2 500 pg / m3(concentration at 0.5 pg / L), mixed with the air conditioner for 10 minutes. (Contaminated plus DHM C) test gas SO2 500pg / m3(at 0.5 pg / L concentration), mix with DHM aerosol (5 mg / L) at a pressure of 40 psi, for 10 minutes. Day 4: half of the animals in the same group had their lungs taken out quickly and photo taken. The remaining half samples were sent for pathological examinations.

[0183] Figure 10A-C show that compared with the control (A), the contaminated group (B) showed severe congestion of the lung organs of the lung margin, after three-day exposure to SO2 500 pg / m3. Compared with the contaminated (B), group (C) displayed significantly reduced pulmonary congestion and no atopic formation of lung margin, with the treatment of DHM mixed with SO2 500 pg / m3. Its appearance was similar to that of the control (A). The pathological sections showed that compared with the control (D), the section (E) of the contaminated group showed severe inflammatory cell infiltration and congestion in alveoli after exposure to SO2 500 pg / m3. The contaminated plus DHM, inflammatory cell infiltration and hyperemia were significantly reduced. The results suggest that DHM can significantly prevent or reduce the damage of air contaminants to lung.

[0184] DHM against human H1N1 virus infection (Figure 11). The prevention of human H1N1 and other respiratory virus infections was tested. We measured the antiviral effect of DHM using 252 (±34) pg / mL human influenza A (H1N1) virus. H1N1 virus particles were co-cultured with dog kidney cells in the medium containing DHM for 2 hours and washed 3 times. After filtration, unbound compounds were removed by the usual culture medium. After the virus particles were collected, the bound and unbound parts of virus-DHM were analyzed by the direct binding assay, and then compared.

[0185] Figure 11 shows that DHM had a dose-dependent inhibitory effect on H1N1 virus infection. The 50% inhibitory concentration (IC50) of DHM against H1N1 is 2.4 pg / mL (8 pM), and the 100% inhibitory concentration (IC100) against H1N1 virus infection is 8 pg / mL (27 pM).

[0186] DHM against respiratory viruses ’ infection (Figure 12). Briefly, the nose-throat swab specimen method was used to induce infection and also collect samples for various respiratory tests for DHM against respiratory virus infection. The viruses include Rhinoviruses and influenza A or B virus. The column in white is control group, the black column is the day 7 result of infected group, and the gray column is day 14 result of infected group. Dark column is the result in day 7 of infected ±DHM group and light column was tested on day 14 in infected + DHM group. Control group A: 100 pl of normal saline (NS) was placed in the mouth and removed the liquid intake for 30 minutes. From the first day, a 0.5x0.5x0.5 cm cube of drug-free gel was given daily for 7 days. Infected group B: 100 pl of viruses’ preparation (culture medium) was placed in the mouth during the experiment and remove the liquid intake for 30 minutes. From the first day, a 0.5x0.5x0.5 cm cube of drug-free gel was given daily for 7 days. The infected + DHM group C: 100 pl of viruses’ preparation (culture medium) was placed in the mouth during the experiment and the mice were removed from the liquid intake for 30 minutes. From day 1, a 0.5x0.5x0.5 cm cube DHM (2 mg) agar was administered twice daily (8 AM and 8 PM) for 7 days.

[0187] On days 7 and 14, all mice were brought in for behavioral tests to measure their activity and mobility after infection. After final measurements, the animals were dissected (Figure 12).

[0188] Compared with control group (A), infected group (B), infected group with 100 pl of viruses’ preparation (medium), showed significantly reduced physical strength in the activity test on day-7 of the activity test, indicating decreased activity ability (Figure 12A). Compared with the infected group (B), the infected +DHM group (C, infection+ DHM) showed a significant increase in activity (bar C). Figure 12B-C represent the animal's unique ability to explore. The infected group showed a remarkable lack of interest in their surroundings. The infected + DHM group showed the same ability to explore as the control group. Compared with the time required for recoveiy after infection, the infected group demonstrated no obvious signs of self-recovery after two weeks of infection.

[0189] However, the infected+ DHM also showed evident physical recovery one week after infection and showed fully recovered physical activity two weeks later.

[0190] Epileptic seizures (Figure 13). The brain controls how the body moves by sending out electrical signals through the nerves to the muscles. Seizures, or convulsions are caused by abnormal electrical activity within the brain, leading to falls, loss of consciousness, airway obstruction, coma, or death. If persistent or prolonged, seizures can potentially cause brain damage. Seizures are different from person to person. Some people have only slight shaking of a hand and do not lose consciousness. Other people may become unconscious and have violent shaking of the entire body. Epileptic seizure: Epilepsy is a nervous system problem that causes seizures. It can develop at any age. About 2.5 million Americans have epilepsy. One of the major underlying mechanisms of pathophysiology of epileptic seizure is ineffective GABA action. Seizure medicines are classified by the type of epilepsy they are used to treat. No one medicine dominates for effectiveness, and all have various side effects. The medications for reducing or stopping non- epileptic seizures or epileptic seizures are limited. Our goal is to find a compound with high efficacy and targeting with minimum side effect. Based on previous studies of DHM, we hypothesis that DHM may also be a candidate for an anti-convulsant therapeutic.

[0191] We did follow studies.

[0192] Study-1 : DHM anti-convulsant effects on Pentylenetetrazol (PTZ)-induced seizures in rats. Rats (SD male) body weight: 210-300g.

[0193] Vehicle group (n=6) were i.p. injected saline (20ml / kg) and PTZ (42mg / kg).

[0194] DHM group (n=6) were i.p. injected DHM 2mg / kg and then PTZ 42 mg / kg.

[0195] After ended injection, timer was started. In vehicle group, 75% rats had seizures and the average seizure duration was 2.87 min; while in DHM group, 50% rats had seizures and the average seizure duration was 0.15 min. p<0.01vs vehicle group. One way ANOVA (Figure 13A). The results indicate DHM effects on PTZ-induced seizures.

[0196] Study-2: All volunteers, who diagnosed Autism with seizures or epilepsy for DHM-anti convulsant study had seizures problem. All volunteers took DHM one pack (5 mg / kg) oral per day for three months. The times of seizures before DHM was used as baseline. Then, we checked the times of seizures the end of a month. Figure 13B shows the times of seizures from 7- 2.5->0.2- 0 09 / day, p<0.05vs before DHM treatment. Data suggest that DHM can reduce seizure symptoms in autism and epilepsy.

[0197] Stroke. Figure 14 shows the image of Grid-walking test. SD adult rat were used for this study. We used our stroke model. Briefly, in day 1, we injected silicone through left carotid artery to surgically make left side brain stroke. We also have sham group as the control. From day 2, we started to apply DHMP 5 mg / kg gavage once per day. Another group, after surgery, rats received saline 2 ml / kg, gavage treatment as drug control. The behavioral assays were done by treatment day (D) 10, 20 and 30.

[0198] In the 5-minute grid-walking test (A), stroke animals can only perform 1 minute, and often drop down from grid. While stroke + DHMP treated rats can perform nearly 3.5 minutes compared with control 3.8 minutes. In open field assay (B), stroke rats can only run a distance of -270 cm, while stroke+DHMP (D-P) treated rats can run -700 cm. Stroke rats were not able to access the center of open field (C) (Figure 14 and Figure 15). The data suggest DHM administration improves brain function after severe stroke.

[0199] Soluble derivatives of DHM.

[0200] The salt-form of DHM, DHM-Piperidine (DHMP, D-P), can be dissolved in water and potentiate GABAARS at 100-fold lower concentration, compared with natural DHM. To evaluate whether DHMP can keep the feature of potentiation of GABAARS, whole-cell voltage-clamped recordings from hippocampal DGCs in slices were performed to test D-P and compared with DHM effects on GABAergic tonic current (Itonic) and miniature inhibitory postsynaptic currents (mIPSCs).

[0201] DHMP potentiates GABAARS at 100-fold lower concentration compared with DHM (Figure 2). Summary of Itonic and mIPSC area potentiated by a DHM-Piperidine (D-P) and DHM from .01 to 10 pM (n = 6 neurons / 3 rats). *p<0.01 vs. ‘0’ drug, f, p<0.01 vs. DHM. We applied DHMP and DHM at concentration of 0.001, 0.01, 0.1, 0.3, 1.0, and 10 pM, respectively. Compared with DHM enhancing GABAergic Itonic from 20 pA (basal Itonic) --40 pA 58 pA — > 70 pA --90 pA (Table 1). The results indicate that D-P can maintain DHM features, increase its potency, bioavailabihty, and efficacy. Table 1. Evaluation of DHMP potency and efficacy vs. DHM on GABA transmission.

[0202] Additional information and data can be found in U.S. Publication No. 2022 / 0387379 and PCT Publication No. WO 2022 / 251116, which applications are incorporated herein by reference.

[0203] DHMP can replicate DHM effects to improve cognition / memory decline in TG-mice. We demonstrated that TG mice show signs of cognition / memory decline. These abnormal behavioral changes are consistent with human studies and are commonly seen in AD patients. In this evaluation study, we used previous methods to test D-P effects (Figure 16).

[0204] Mice were divided into four groups: (1) C57BL / 6 wt male mice were treated with oral administration of 2 % sucrose (SUC); (2) C57B1 / 6 wt male mice with oral administration of 1 mg / kg D- P in 2 % sucrose; (3) TG-mice with oral administration of 2 % sucrose; and (4) TG-mice with 1 mg / kg D-P in 2 % sucrose. After 3 months of treatment, the recognition memory of mice was evaluated with NOR tests (Figure 16A and Figure 16B). The wt control spent more time exploring the novel objects (ORI = 68.9 ± 6.8 %). ORI was reduced to 51.2 ± 3.6 % in TG-mice. The wt of mice treated with D-P exhibited recognition similar to the wt control. D-P significantly improved NOR (ORI = 70.1 ± 6.8 %) in TG-mice. Next, we evaluated NCR (Figure 16C). The RI was calculated. Compared with the wt control, the TG-mice exhibited reduced RI (49.2 ± 2.6 %). D-P treatment reversed the RI in TG-mice and showed significant contextual memory improvement. These results indicate that daily oral application of D-P could replicate DHM effects and improve recognition memory in the TG-mice of AD.

[0205] DHMP can replicate DHM effects to improve behavioral impairment in TG-mice (Figure 17). We examined the effect of D-P on AD symptom-like behavior in aged TG2576 mice compared with age-matched wt. mice. Mice were divided into three groups: (1) C57BL / 6 wt. male mice (2 % sucrose, oral administration), (2) TG-mice (2 % sucrose, oral administration), and (3) TG-mice with D-P (2 mg / kg in 2 % sucrose), respectively. After 3 months of treatment, mice were examined with behavioral assays.

[0206] Locomotor activity was assayed with open field test. Running distance is one of the parameters quantifying locomotor activity (Figure 17A). Wt. control mice ran 882 ± 55 cm during 10 mm. TG- mice ran a much shorter distance (255 ± 12 cm), while the running distance of TG-mice treated with D- P increased to 611 ± 99 cm. Control mice showed frequent rearing (22.4 ± 3.4 times), explored the center of the open field 2.0 ± 0.6 times, and stayed at the center for 0.14 ± 0.1 min (Figure 17B-C). The TG-mice showed rearing 12.5 ± 2.1 times, explored the center of the open field (0.2 ± 0.1 times), and stayed at the center for only 0.02 ± 0.01 mm. D-P treatment in TG-mice increased rearing (19.3 ± 2.0 times), times to explore the center (1.3 ± 2.0 times), and duration to stay at the center (0.13 ± 0.03 min). The results suggest that the TG-mouse of AD decreases exploratory / locomotor activity. Daily oral D-P treatment for TG-mice improves locomotor activity and increased exploring activity, an instinct of animals. Anxiety was assayed with the EPM (Figure 17D). The wt. control spent 48.5 ± 7.5 % of total time in open arms and 33.5 ± 3.2 % in closed arms. The TG-mice spent a significantly shorter time in open arms and a longer time in closed arms than those of the wt. control, while the TG±D-P mice spent a similar amount of time in each arm.

[0207] These results indicate that TG-mice exhibit apathy-like behavior deficits, and anxiety. D-P treatment daily ameliorates and prevents these symptoms. These results are consistent with the notion that behavioral D-P actions involve GABAARS and that the GABAergic system contributes to behavioral changes in AD.

[0208] Oral DHMP daily at dosages of 1, 10, and 100 mg / kg in a two-week study of Functional Observational Battery (FOB) in Rats did not find any notable negative changes (Figure 18). FOB is a neurobehavioral assessment tool describing various behavioral activities related to the application of a drug. Experimental parameters include:

[0209] The doses of DHMP: D-P 1 mg / kg, 10 mg / kg, and 100 mg / kg. Preparation of DHMP: 5% sucrose used for diluting DHMP.

[0210] Animal and treatment: Sprague Dawley (SD) rats (male, body weight 210 ± 20g; female, body weight 200 ± 20g. n=5 / group / gender). Each rat received oral sucrose (SUC) or DHMP application every day for two weeks.

[0211] Animal groups: Control group received 5% sucrose (SUC. 2 ml / lOOg body weight). D-P 1 mg / kg group (D-Pl), D-P 10 mg / kg (D-P10), and D-P 100 mg / kg (D-P100).

[0212] Test procedure: Grid-Walking and Open Field tests were used to evaluate functional capabilities. After the first dose of treatment, we performed behavioral tests, including the Grid walking test (Figure 14) and open field test. We also recorded all rats’ responses to handling and measured body temperature, heartbeat, and breathing ratio every other day. On day 1, we applied SUC or D-P 1 mg / kg, D-P 10 mg / kg, and D-P 100 mg / kg gavage, and then the behavioral assays were performed. Figure 18 shows the results from the Grid-walking test and locomotor activity by open field test.

[0213] Tests: In the 5-minute Grid-Walking test (Figure 18A male, and Figure 18C female), all rats from different groups showed equal performance time on the first day (76% ± 8 in males, and 75% ± 8.5 in females) after the first treatment. After 14 days of treatment, all groups of rats continued to show an equal performance time (76% ± 8.5 in male, and 74.5% ± 9 in females). In the 10-minute open field test (Figure 18B male, and Figure 18D female), all groups of rats showed equal distance movement in the locomotor activity performance (1035 ± 155 cm in males, and 1022 ± 135 cm in females) on the first day after the first treatment. After 14 days of treatment, groups of rats continued to show equal distances in locomotor activity performance (1025 ± 155 cm in males, and 1016 ± 165 cm in females).

[0214] Summary of Observations: During the two weeks, we checked all animals’ fur, response to handling, etc. All rats showed no loss of fur or responses against handling. No deaths or injuries were observed during the experiment We also made sure to observe the animals continuously for 4 hours after each treatment. We mainly focused on the animal's mental behavior, autonomous activity, hair, glandular secretion, feces, death, etc. any negative changes. We found no notable changes with these evaluations. The results indicate that DHMP is a safe compound.

[0215] The FOB parameters, including body temperature, heartbeats, and breathe ratio in rats, are shown in Table 2.

[0216] Table 2. FOB parameters in male and female rats after DHMP.

[0217] T: temperature, °C. P: Pulse, beats / minute. B; breath / minute.

[0218] Oral DHMP daily at dosages of 1, 10, and 500 mg / kg in a six-month long-term evaluation study, DHMP did not alter the metabolic rate (Figure 19). To evaluate D-P’s safety, we tested dosages of 1, 10, and 500 mg / kg of D-P in rats. 500 mg / kg is 500-time higher than the therapeutic dose of DHM. Sprague Dawley rats, male, body weight starting at 175±5g, were used in this study. Control group rats were gavaged SUC 20ml / kg, and D-P group rats were gavaged 1, 10, and 500 mg / kg D-P every day for six months. Compared with control group rats, D-P did not affect body weight growth, food intake, water intake, amount of feces, and amount of urination, D-P does not affect metabolic rates (Figure 19). This result indicates that D-P in high doses is safe for oral everyday application without obvious toxic effects in high doses.

[0219] Effect of DHMP on GABA potentiation in HEK cells (Figure 20). Recombinant Human Embryonic Kidney (HEK) 293 cell line (HEK293 cells) was used to evaluate whether DHMP can keep the feature of potentiation of GABAARS. GABA a5|33y2 were transferred to a chamber perfused with an extracellular solution containing (in mM): 137 NaCl, 5 KC1, 2 CaC12, 1 MgC12, 20 glucose and 10 HEPES (pH 7.40, room temperature), and visualized with an inverted microscope (TE200, Nikon).

[0220] Selected doses of DHMP: 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, and 10 pM were selected. n=6 ~10 cells / group. One cell used only for one concentration recording.

[0221] Whole-Cell Patch-Clamp Recording: HEK293cell expressed with GABA a5p3y2 cells were whole-cell voltage-clamped at a holding potential of -70 mV with an Axopatch 200B amplifier (Molecular Devices, Sunnyvale, CA). The flow rate of the perfusion system was around 3 ml / min, and the total volume of the recording chamber was 3 ml. For GABA concentration-response curves, evoked GABAAR-currents were recorded during acute applications of GABA or DHM onto the cultured HEK293 cells expressed with GABA a503y2. The result indicates that DHMP potentiates GABAARS dose-dependently in HEK293.

[0222] Oral DHMP daily at dosages of 1, 10, and 100 mg / kg in 3rdweek of pregnancy, studying DHMP effects on pregnancy and offspring ’s bodyweight and number of genders in rats (Figure 21). The pregnancy period of SD rats is 21 days, and DHMP was orally administered to female rats during the 3rdweek of pregnancy. Experimental parameters include:

[0223] The doses of DHMP (D-P): D-P 1 mg / kg, 10 mg / kg, and 100 mg / kg. Preparation of DHMP: 5% sucrose was used for diluting DHMP.

[0224] Animal and treatment: Sprague Dawley (SD) rats (dam, body weight 200 ± 20g. n=5 / group / gender). Each rat received oral sucrose (SUC) or DHMP application every day for 5 days.

[0225] Animal groups: Control group received 5% sucrose (SUC. 2 ml / lOOg body weight). D-P 1 mg / kg group (D-Pl), D-P 10 mg / kg (D-P10), and D-P 100 mg / kg (D-P100). Offspring body weight (BW) and numbers of sex in SD pregnant rats after DHMP administration were measured. We weighed body weight (Figure 21A) and counted offspring numbers (Figure 21B) after new-bum 5 days. The results indicate that DEIMP is a safe compound for pregnancy and neonates.

[0226] Effect of DHMP on plasma [EtOH] in rats (Figure 22). Plasma EtOH-DHMP BAC from SD- Rats. For testing DHMP effects on reducing [EtOH] in serum, alcohol 3 g / kg and alcohol 3 g / kg plus DHMP 1 and 5 mg / kg, respectively, were orally administered to rats. The blood was sampled before administration, after alcohol at the time point 5, 60, 90, 120, 150, 180, 240, 300, 360 minutes, and 24 hours. At 5 min after alcohol 3 g / kg, the blood [EtOH] reached 250 mg / dl. Animals quickly started Loss of Righting Reflex (LORR). While DHMP 1 mg / kg reduced [alcohol] to 190 mg / dl, and DHMP 5 mg / kg reduced [EtOH] to 96 mg / dl. DHMP groups did not show LORR. After alcohol 3 g / kg, the [alcohol] in alcohol group still in the high levels of above 150 mg / dl. While DHMP groups’ [EtOH] levels became below 100 mg / dl at 3-hour (D-P 5 mg / kg group) and 4-hour point (D-P 1 mg / kg group). The results indicate that DHMP effects on reducing [EtOH], Effect ofDHMP on plasma [EtOH] human (Figure 23). Plasma EtOH-DHMP BAC from human (IRB ID 2023LL01). For testing DHMP effects on reducing [EtOH] in serum of human, we have 30% alcohol plus placebo, 30% alcohol plus DHMP 1 mg / kg, and control (without placebo or DHMP) groups. Before and after alcohol 15 minutes, after alcohol 30 minutes, 1-hour and 5-hour time points, we collected blood samples. Figure 23A shows ethanol levels ([EtOH]) at the different time points. After 30-minute alcohol treatment, the [EtOH] increased to 200 mg / dl in placebo group, while [alcohol] reached 150 mg / dl in DHMP group. After 5-hour alcohol treatment, [EtOH] was still staying around 160 mg / dl, while [EtOH] was reduced to 50 mg / dl in DHMP group. The results indicate that DHMP effects on reducing [EtOH], After 2-hour alcohol, we also tested behaviors using the straight- line score and hangover sign sheet. Walking straightly will be scored 10. Once out of line will be reduced 1 score. Compared with placebo group, DHMP group could perform perfectly straight-line walking (Figure 23B). Also, DHMP group didn’t complain hangover signs. The results indicate that DHMP reduces [EtOH] in blood and counteracts alcohol induced side effects in humans.

[0227] Conclusions. The preparation method of DHM ammonium compounds as described herein enables each DHM ammonium compound to exhibit different degrees of dissociation. The preparation method of the DHM ammonium compounds enable the DHM ammonium compounds to have different degrees of dissociation. New DHM-denved compounds can increase DHM bioavailability, increase its potency, efficacy, and improve water solubility. New DHM-derived compounds maintain DHM effects improving cognition / memory decline in TG-mice. Furthermore, new DHM-derived compounds maintain DHM effects improving behavioral impairment in AD-mouse model. The indications for DHM compounds can be, for example, sleep problems / trouble sleeping, anxiety / depression / anxiety disorders, early stages of Alzheimer’s disease / dementia / Parkinson disease, and other neurodegenerative diseases.

[0228] The DHM-derived compounds described herein have been found to be safe. Oral D-P daily at dosages of 1, 10, and 100 mg / kg in a two-week study of FOB in rats did not find any notable negative changes. The DHM compounds are safe for everyday oral application without toxicity, even with administration at high doses. With daily oral D-P administration at dosages of 1, 10, and 500 mg / kg in a six-month long-term evaluation study, D-P did not alter the metabolic rate. The DHM-derived compounds can be used for AUD, FAS, alcohol-liver disease, and mental disorders including anxiety, depression, PTSD, epilepsy, neurodegenerative diseases, especially ADRD, and Autism. The dosage / concentration range can be from 0.5 mg / kg to 500 mg / kg, and 0.1 nM to 100 pM.

[0229] Lack of medications for intervening and treating early onset Alzheimer ’s disease and related dementias.

[0230] Alzheimer’s disease (AD) and related dementias (ADRD) are debilitating conditions characterized by cognitive decline and memory loss, profoundly impacting daily functioning and overall quality of life. The intricate web of pathologies involves:

[0231] 1) Accumulation of amyloid-P (A0) plaques and tau tangles: These disrupt brain cell function. 2) Neuroinflammation: Triggered by immune responses and oxidative stress, which compound cellular deterioration.

[0232] 3) Mitochondrial dysfunction: Disrupts energy production and waste removal, contributing to protein misfolding challenges within the brain.

[0233] 4) Synaptic dysfunction: Leads to communication breakdown between neurons and cognitive decline.

[0234] 5) Imbalances in neurotransmitter levels and diminished brain blood flow: Further erode cognitive abilities. Genetic factors also contribute to disease onset and progression. These multifaceted factors underscore the urgency to comprehensively understand and target the intricate interplay of these mechanisms in the pursuit of effective treatments.

[0235] Genetic factors also contribute to disease onset and progression. These multifaceted factors underscore the urgency to comprehensively understand and target the intricate interplay of these mechanisms in the pursuit of effective treatments.

[0236] Despite more than a century of efforts, no current treatments can stop or reverse the progression of early-onset Alzheimer’s disease, though some may temporarily improve symptoms. Therapeutic approaches aimed at reducing A levels have proven ineffective in clinical trials. Investigations into the impact of Rivastigmme, a cholinesterase inhibitor, and Varenicline, a partial agonist of the a4 2 subtype of the nicotinic acetylcholine receptor, on daily activities and cognition among AD patients have yielded modest or negligible enhancements compared to placebo. While Memantine is employed to address AD with mild cognitive impairment, a comprehensive analysis of numerous evaluations has shown that it does not enhance cognitive function or capabilities in those with mild cognitive impairment and is associated with an increased risk of gastrointestinal adverse effects.

[0237] Clinical trials focusing on new drugs for AD were documented in 2020, but subsequent developments have emerged since then. Notably, the US-FDA has approved Lecanemab and donanemab, both antibodies targeting amyloid, marking the end of a nearly two-decade period without new AD drugs. The two antibody drugs reduce the accumulation of amyloid plaques and slow down the decline of cognition but do not improve cognition and memory. These drugs do not revers nor stop the progression of the disease. These drugs have known site effects such as infusion site reaction, which can cause pain or swelling. . As such, a novel and / or alternative approach is urgently needed.

[0238] Human studies have revealed that, in addition to cognitive decline, memory loss, and impaired learning, a significant proportion of AD patients experience other neuropsychological symptoms. Up to 45% of AD patients experience anxiety and depression, and 17% have seizures. This suggests compromised GABAergic transmission, characterized by an imbalance between excitatory and inhibitory signaling in the brain. Activation of GABAARS has been shown to counteract AP-induced excitotoxicity, thereby diminishing network excitability. Given that GABAARS play a pivotal role in synaptic plasticity essential for normal cognition, the abnormal network activity associated with synaptic loss contributes to cognitive deficits observed in AD. However, how GABAARS contribute to pathogenesis in AD is still unknown.

[0239] GABAARS, the primary inhibitory neurotransmitter, modulate the delicate equilibrium between excitation and inhibition in the brain. GABAergic transmission plays a pivotal role in diverse cognitive functions, including attention, memory, and overall brain activity. The transmission of GABA is crucial for maintaining neuronal stability, serving as a critical safeguard against the potential hazards of excessive excitotoxicity that can lead to detrimental outcomes. There are no GABAergic drugs for treating AD to this day.

[0240] Astrocytes, the most prevalent glial cells in the brain, play a variety of roles in the healthy brain, including neurogenesis, immune functions, blood-bram barrier (BBB) integrity, and learning and memory. Astrocytes play an essential role in the GABAergic system by participating in the formation of tripartite synapses, a fundamental unit for memoiy and cognitive function. Through the formation of GABAergic tripartite synapses, astrocytes contribute to the intricate web of communication that underlies memory and cognition. The persistent glial cell-mediated neuroinflammation is the primary cause of both neurodegenerative processes and cognitive deficits in AD patients. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system (CNS). Studies have shown that neuroinflammation, characterized by immune responses within the CNS, is closely associated with the pathological hallmarks of AD, exacerbating neuronal loss and cognitive decline. Unfortunately, anti-neuroinflammation drugs are not available for AD.

[0241] Despite over a century of research, effective and useful medications for AD are still lacking, particularly those addressing GABAergic dysfunction and neuroimmune impairment in AD. While the FDA has approved several medications for treating AD, their clinical effects have shown to be minimal to none. Despite thousands of clinical trials, no medications have been identified that can halt, prevent, or significantly improve AD symptoms. This situation underscores the urgent need for breakthroughs in AD research and treatment.

[0242] DHM for Treating Alzheimer ’s Disease. Our team has developed dihydromyricetin (DHM), derived from Ampelopsis, as a positive allosteric modulator (PAM) of GABAergic transmission. Unlike benzodiazepines (BZs), another modulator of GABAergic transmission, DHM does not exhibit addictive properties or tolerance potential. Our investigations have shown that DHM alleviates stress, anxiety, seizures, and sleep problems, while also reversing neuropathological changes associated with cognitive impairment in AD.

[0243] Our recent studies provide compelling evidence that tripartite synapses, involving astrocytes, pre-synapses, and post-synapses, are fundamental for cognition. Damage to tripartite synapses is a key mechanism for cognitive impairment, making GABAergic tripartite synapses a potential target for AD and related dementias (ADRD) therapeutic approaches. Human studies indicate that up to 45% of individuals with AD experience anxiety, and around 17% have seizures, along with nearly 100% reporting sleep disorders in addition to cognitive / memory loss and impaired learning. This suggests compromised GABAergic transmission in AD. Activation of GABAARS has been shown to counteract AP-induced excitotoxicity, reducing network excitability. GABAARS play a pivotal role in synaptic plasticity essential for normal cognition, and abnormal network activity due to synaptic loss contributes to cognitive deficits in AD. Based on this evidence, our research has focused on systematically developing GABAergic drugs.

[0244] Astrocytes are the most prevalent glial cells in the brain and play a variety of roles in the healthy brain, including in neurogenesis, immune functions, blood-brain barrier (BBB) integrity, and learning and memory. Astrocytes play an essential role in the GABAergic system by participating in the formation of tripartite synapses, a fundamental unit for memory and cognitive function. Through the formation of GABAergic tripartite synapses, astrocytes contribute to the intricate web of communication that underlies memory and cognition. The persistent glial cell-mediated neuroinflammation is the primary cause for both neurodegenerative processes and cognitive deficits in AD patients. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system (CNS). The studies have shown that neuro-inflammation, characterized by immune responses within CNS, is closely associated with the pathological hallmarks of AD, implicated in exacerbating neuronal loss and cognitive decline. Therefore, microglia and astrocytes are key regulators of inflammatory responses in AD. Unfortunately, anti-neuroinflammation drugs are not available for AD.

[0245] Given that AD progresses slowly and is a major cause of dementia, early symptom identification is crucial. Social isolation has been linked to a 50% increase in AD risk (as of 2020) due to its detrimental effects on neural and immune systems. Animal models subjected to a 4-week isolation period exhibited increased A0 plaques, tau tangles, neuroinflammation, reduced gephyrin and GABAergic neurotransmitter activity, and behavioral changes such as anxiety / aggression and cognitive decline. DHM shows promise in reversing these pathological changes, indicating its potential as a valuable intervention and therapeutic for AD.

[0246] Development of DHM-cmalogs, apDHMs and aA-DHMs. DHM is a natural compound that shows promise in reversing pathological changes in AD. However, we are aware of its limitations, including low bioavailability, solubility, and stability. Therefore, we have developed DHM analogs to address these issues. Since its development in 1945 as a natural compound, DHM has been recognized as a valuable resource in daily life. Despite numerous studies on DHM, modulating its properties without introducing negative effects remains a significant challenge. Maintaining its benefits and features while overcoming its limitations is a complex task that continues to challenge pose difficulties for chemists. We have developed two important analogs of DHM: phosphorylated DHM ("apDHMs"), and a- amine substituted DHM ("aA-DHMs"). To keep DHM’s original properties without introducing negative effects, we focused on modifying at the a-position of the ketone for the following reasons: the reaction conditions are mild, and the yield of the coupling reactions ranges from moderate to good; the a position of the ketone is easily modified with high chemical selectivity, and modification on this site reserves the H-acceptor ketone that is important for the bioactivity of the compound; and the modification will enhance interactions with the targeting protein with an amphoteric chain.

[0247] Phosphorylation is an organic process that adds a phosphate group to a compound. This process is crucial in biochemistry and molecular biology, playing a key role in many areas, including protein and enzyme activity, sugar metabolism, energy storage and release, and the cellular transfer of free energy. In biological systems, phosphorylation involves adding a phosphoryl (PO3) group to a molecule, which is essential for cellular energy storage and transfer.

[0248] An amino group is a functional group consisting of a nitrogen atom bonded to two hydrogen atoms. Adding an amino group to an organic compound forms an amine. Biogenic amines are low- molecular-weight organic bases that are formed and degraded as part of normal metabolism. These biogenic amines play several physiological roles in humans, such as aiding gut digestive enzymes and microbes, which are crucial in regulating intestinal functions, including digestion, absorption, and local immunity.

[0249] Due to the modifying position and these unique physicochemical properties of phosphoryl and amine groups, the introduction either of these two groups will significantly improve the solubility, bioavailability, and keep DHM’s activity without introducing negative effects. The series of apDHMs and aA-DHMs are more efficacious and potent at potentiating GABAARS than DHM, without inducing tolerance. DHM-analogs have better physiochemical properties and drug-likeness. Our studies of the series of apDHMs & aA-DHMs target GABAergic-tripartite-synapses-neuroinflammation, a critical pathway contributing to cognitive decline, instead of the conventional targeting of AP peptides. The hypothesis of GABAergic-tripartite-synapses-neuroinflammation has been established by our studies.

[0250] Targeting GABAergic-tripartite-synapses-neuroinflammation, our team has found that modulated DHM-compounds improved anxiety / aggression and cognitive / memory deficits as well as reversed pathologies including GABA dysfunction, neuroinflammation, and accumulation of brain Ap and pTau. DHM-analogs show promise as an effective lead candidate for intervention and treatment for AD and related dementias, particularly for cognitive / memory deficits in patients in early onset with mild to moderate symptoms of AD.

[0251] As analogues of DHM, apDHMs and aA-DHMs show increased potency, efficacy, enhanced chemical stability, and remarkable pharmacological activity. The capacity to upregulate gephyrin- GABA levels and reduce inflammation align with improved cognitive impairment and a reduction in anxiety / aggression in both TG- and Si-induced cognitive decline mice models. These findings position DHM-analogs as promising candidates for preventing and treating cognitive / memory deficits in AD and related dementias, and also for the disease or disorder of the immune-system and glutamate- system / GABA-system imbalance, or symptoms.

[0252] Dietary Supplement and Nutraceutical Formulations.

[0253] The compounds, extracts, and compositions described herein can be used to prepare supplements, nutraceuticals, and therapeutic compositions, for example, by combining the compound, extract, or composition with food or with an acceptable diluent, excipient, or carrier. The compounds or extracts may be added to a carrier in the form of a salt or solvate. For example, in cases where compounds are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate. Examples of acceptable salts are organic acid addition salts formed with acids that form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a-ketoglutarate, and P-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, halide, sulfate, nitrate, bicarbonate, and carbonate salts.

[0254] Salts and complexes may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid to provide a physiologically acceptable ionic compound. Alkali metal (for example, sodium, potassium, or lithium) or alkaline earth metal (for example, calcium) salts of carboxylic acids or amino acids can also be prepared by analogous methods.

[0255] The compositions described herein can be formulated as supplements or nutraceutical compositions and administered to a mammalian host, such as a human patient, in a variety of forms. The compositions can be specifically adapted to oral administration.

[0256] The compositions described herein may be administered in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. For oral administration, compositions can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or incorporated directly into the food of a patient's diet. Compositions may also be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations typically contain at least 0.1% of active compound. The percentage of the compositions and preparations can vary and may conveniently be from about 0.5% to about 60%, about 1% to about 25%, or about 2% to about 10%, of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions can be such that an effective dosage level can be obtained.

[0257] The tablets, troches, pills, capsules, and the like may also contain one or more of the following: binders such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid and the like; and a lubricant such as magnesium stearate. A sweetening agent such as sucrose, fructose, lactose or aspartame; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring, may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and flavoring such as cherry or orange flavor. Any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0258] Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can be prepared in glycerol, liquid polyethylene glycols, triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil. Under ordinary conditions of storage and use, preparations may contain a preservative to prevent the growth of microorganisms.

[0259] The ultimate dosage form should be sterile and stable under the conditions of manufacture and storage. A liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceiyl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions, or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and / or antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers, or sodium chloride.

[0260] Useful solid earners include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, dimethyl sulfoxide, alcohols, glycols, or water-alcohol / glycol blends, in which a compound can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be taken orally or by other effective means.

[0261] Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified mineral materials can be included in the formulations.

[0262] Useful dosages of the compositions described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Patent No. 4,938,949 (Borch et al.). The amount of a compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of an attendant physician or clinician.

[0263] The compound is conveniently formulated in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form. In one embodiment, the present technology provides a composition comprising at least 100 mg of DHM or DHMP per dosage form. The desired total daily dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, or four sub-doses per day. The sub-dose itself may be further divided, e g., into a number of discrete loosely spaced administrations.

[0264] The compositions described herein can be effective agents for insomnia, anxiety and cognition decline and have higher potency and / or reduced toxicity as compared to DHM or Hovenia extract. The ability of a compositions to treat insomnia, anxiety and cognition decline may be determined by using assays well known to the art.

[0265] The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention.

[0266] EXAMPLES

[0267] Example 1. Representative procedure of salt-formulations with DHM.

[0268] DHM (1.6 g, 5.0 mmol, HPLC grade, 99%. Master Herbs LLC. Los Angeles, USA) was dissolved in MeOH (20 ml) at room temperature for 30 min and then was cooled in an ice bath. To prepare this mixture, a solution of nature amino acid (Arginine or Lysine) (10 mmol) or amino compounds (di ethylamine, piperidine or tri ethyl amine) in MeOH was added dropwise at -10 °C under argon and then was allowed to warm to room temperature. After the reaction was completed, the resulting mixture was concentrated under reduced pressure to give a residue. The residue was filtered and washed by MeOH 3 times to provide the desired product (Scheme 1).

[0269] DHM-Piperidine Complex: pipendin-l-ium (2R, 3 / ?)-2-(3,4-dihydroxy-5-oxidophenyl)-3,5- dihydroxy-4-oxochroman-7-olate (MW: 405.40).

[0270] DHM-Di ethyl amine Complex: diethylammonium (2 / ?.3 / ?)-2-(3,4-dihydroxy-5-oxidophenyl)- 3,5-dihydroxy-4-oxochroman-7-olate (MW: 393.39).

[0271] DHM-Tri ethylamine Complex: tri ethylammonium (2 / ?.j / ?)-2-(3,4-dihydroxy-5-oxidophenyl)- 3,5-dihydroxy-4-oxochroman-7-olate (MW: 623.83). DHM- Arg Complex: (5)-amino((4-amino-4-carboxybutyl)amino)methaniminium (2R, 3R)-2- (3,4-dihydroxy-5-oxidophenyl)-3,5-dihydroxy-4-oxochroman-7-olate (MW: 1017.07).

[0272] DHM-Lys Complex: (ri)-5-ammo-5-carboxypentan-l-amimum (2 / ,3 / )-2-(3,4-dihydroxy-5- oxidophenyl)-3,5-dihydroxy-4-oxochroman-7-olate (MW: 466.44).

[0273] Scheme 1. Salt-forms of DHM.

[0274] DHM-Arg Complex DHM-Lys Complex

[0275] MW:1017.07 MW: 466.44

[0276] Example 2. Preparation of derivatives of DHM.

[0277] We have designed, developed, and characterized 5-hydrooxy-7-methoxy-3-(4-(l- methylpiperidin-4-yl)butyl)-2-(3,4,5-trimethoxyphenyl)chroman-4-one (DHM-Piperidine (DHMP)), based on our earlier formulations of DHM shown in Example 1. We found that DHMP has improved potency, efficacy, and drug-properties compared to DHM (see Figure 1-2 and Table 3).

[0278] Table 3. Comparison of pharmacokinetic and physicochemical properties of DHM and DHMP. Scheme 2. Preparation of DHMP (see Figure 3 for plasma concentration data).

[0279] Scheme 3. Preparation of DHME (see Figure 3 for plasma concentration data).

[0280] 1-1

[0281] Synthesis Procedure of ap-DHMs. Dissolve potassium carbonate (6.0 eq ) and dihydromyricetin (1.0 eq ) in DMF, stir the reaction for 30 min, then add methyl iodide (8.0 eq ) and stir overnight at room temperature. After the TLC monitoring reaction was completed, the reaction solution was diluted with water, extracted with EA, the organic phase was collected, dried with anhydrous Na2SC>4, and the product was obtained by column chromatography. Compound 1-1 is obtained.

[0282] To a stirred solution of compound 1-1 (1.0 eq) and phosphorus oxychloride (5.0 eq) in Trimethyl phosphate mixture was stirred for 6 h at 0°C, and then ROH (5.0 eq) was added while stirring was continued for additional 30min. After this time, the mixture was diluted with water. The residue was punfied via preparative HPLC (C18-A column, 150x10.0 mm, 5 pm) (mobile phase A: 0.1% trifluoroacetic acid (aq.), mobile B: 0.1% trifluoroacetic acid in methanol; flow rate = 2.0 ml min-1; 0- 5min: 0-25% B, 5-12 min: 25-45% B, 12-17 min: 45-100% B, 17-20 min: 100-25% B). Compound 1-2 is obtained.

[0283] To a solution of compound 1-2 in dry DCM was added tribromoborane (5.0 eq) dropwise under nitrogen at -78°C. After addition, the reaction solution was stirred at room temperature overnight. Then the mixture was cooled to -78°C, and then water was added dropwise to it until no gas was liberated. The reaction mixture was then extracted with DCM, then EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain product Compound 1-3: apDHM.

[0284] Scheme 7. The New Compounds’ Structures of ap-DHMs.

[0285]

[0286] “A-DHM

[0287] Synthesis Procedure of aA-DHMs. The compound 1-1(1.0 eq), DEAD (3.0 eq), triphenylphosphine (3.0 eq) was dissolved in dioxane, and then the RNH2 (1.5 eq) was added under an ice bath, raised to room temperature, the reaction was overnight, and after the TLC monitoring reaction was completed, column chromatography was obtained, and the compound II- 1 was obtained. To a solution of Compound II- 1 in dry DCM was added tribromoborane (5.0 eq) dropwise under nitrogen at -78°C. After addition, the reaction solution was stirred at room temperature (~21 ±1 °C) overnight. The mixture was then cooled to -78 °C and water was added dropwise until no gas was liberated. The reaction mixture was then extracted with DCM, then EA. The organic layer was washed with brine, dried over Na2SC>4 and concentrated to obtain product Compound 1-3. Scheme 9. The Structures of aA-DHMs.

[0288] Example 3. Methods.

[0289] Whole-Cell Patch-Clamp Recordings from Brain Slices. Transverse slices (400 pm) of dorsal hippocampus were obtained from wt and TG-SwDI mice (male, 20 months old) using a vibratome (VT 100; Technical Products International). Slices were perfused continuously with artificial CSF (ACSF) composed of the following (in mM): 125 NaCl, 2.5 KC1, 2 CaCl2, 2 MgCl2, 26 NaHCCh, and 10 D- glucose. The ACSF was bubbled continuously with 95%C>2 / 5% CO2 to ensure adequate oxygenation of slices and a pH of 7.4 and kept at 34 ± 0.5 °C for perfusion. TTX (0.5pM), APV (40 pM), CNQX (10 pM), and CGP54626 (I M, GABABR antagonist) were added to ACSF to pharmacologically isolate GABAAR-mediated mIPSCs. Patch electrodes were filled with internal solution containing the following (in mM): 137 CsCl, 2 MgCl2, 1 CaCl2, 11 EGTA, 10 HEPES, and 3 ATP, pH adjusted to 7.30 with CsOH. Recordings targeted dentate gyrus granule cells (DGCs) of hippocampal slices. Voltageclamp whole-cell recording was performed using a patch clamp amplifier 3) EPM: All animals were tested anxiety levels on EPM. Animals were placed on the central area of the maze, tested for 5 min. and video recorded. The following measures were scored: number of entries into open arms, closed arms, or center platform and time spent in each of these areas. Data were reported as % of number of entries in arms, % of time spent in different entries, and number of total entries.

[0290] Memory Test Protocol. Novel Object Recognition (NOR): Day 1-3: Habituation (once / day). Top open containers (open field) were used with video camera to record animal behavior. An animal was put into a container with no objects for 5 min. Context remained exactly the same for each animal. Day 4: Familiarization. Two identical objects (toys-FO: familiar object) were put into the container at specific positions. Then animals were put into the container to explore the objects for 5 min. Retention Trial 1.5 h: Each animal was placed in its home cage for 1.5 h after the familiarization. One of the toys was replaced with a new toy (NO, novel object and very different from FO). Then we put an animal into the container with the obj ects for 3 min and videotaped it for offline scoring. The score was based on how long animals spent exploring each toy. The pair of objects in a set was tested previously to avoid the natural preference of the mice for shape or light reflection; we used 4 sets of objects in total for this test. Day 5: Retention Trial 24 h. We placed another new toy (NO) along with an original object (FO) in the container. Then we put an animal into the container and tested it for 3 min. We scored the animal behavior offline according to how long the animal spent exploring each object. The Object Recognition Index (ORI) was calculated, such that ORI = (tn - tf) / (tn + tf), where tf and tn represent times of exploring the familiar and novel objects, respectively.

[0291] Novel context recognition (NCR): Day 1-3 was Habituation (once / day). Two contexts (containers) A and B with similar field area were very different in shape. Context A was a rectangular, Context B was a circular container. The containers were open at the top with bedding to minimize stress and with video camera on top to record animal behavior. Each animal was placed in Context A without toys for 5 min, then back to home cage for 30 min. Then the animal was placed in Context B without toys for 5 min. Day 4 was for Familiarization. Two different sets of toys were used as the familiar objects referred to as FO1 and FO2 respectively. Each set consists of two identical toys while FO1 and FO2 were very different in shape. The two toys of FO1 were each placed in a specific position in Context A. Each animal was placed in Context A and allowed to explore FO1 for 5 min; then animal was back to home cage for 30 min. The two toys of FO2 were each placed in a specific position in Context B. Each animal was placed in Context B and allowed to explore FO2 for 5 min. Day 5 (24 h from familiarization): Retention Trials were performed to determine the memory retention of each animal for familiarized objects. One toy of FO1 in Context A was exchanged for one toy from FO2. Then each animal was allowed to explore the objects in Context A for 3 min. The test was videotaped and analyzed offline. The time spent exploring the familiar object (FO1) and exchanged object (FO2) were calculated where exploration equals touching the object with nose or paws or sniffing within 1.5 cm of the object. Recognition Index (RI) was calculated with formula; Index = (tn - tf / (tn + tf), where tf represents the time of exploring the familiar object previously encountered in the same context and tn represents the time of exploring the object in a different context. Increased exploration of the object presented in a different context over the object previously encountered in the same context was interpreted as increased formation of contextual memory.

[0292] Locomotor assay. In order to measure the locomotor activity, the numbers of total entnes were measured for each animal. Statistical differences were determined using ANOVA. These experiments determined the effects of D-P on motor function and anxiety levels.

[0293] Elevated plus maze assay (EPM). Performed in a quiet and dark room with only a low power red light. Rats were placed on the central area of the maze, and their behavior video recorded for 5 min. The number of entries into open arms, closed arms, or center platform and time spent in each of these areas were scored during off-line analysis. Data were reported as % of number of entries in arms, % of time spent in different arms, and number of total entries. These experiments determined the effects of D-P on anxiety levels.

[0294] Example 4. Dosage Forms.

[0295] The following formulations illustrate representative dosage forms that may be used for the administration of a compound or composition generally or specifically disclosed herein (hereinafter referred to as 'Compound X'). As would be readily understood by one of skill in the art, the quantities in the following compositions can be adjusted to provide compositions having higher or lower total quantities, for example, to obtain dosage forms having at least 100 mg of DHMP, or about 300 mg of DUMP, by adjusting the amount of each recited component proportionally.

[0296] (i) Tablet 1 mg / tablet

[0297] 'Compound X' 100.0

[0298] Lactose 77.5

[0299] Povidone 15.0

[0300] Croscarmellose sodium 12.0

[0301] Microcrystalline cellulose 92.5

[0302] Magnesium stearate 3,0

[0303] 300.0

[0304] (ii) Tablet 2 mg / tablet

[0305] 'Compound X' 20.0

[0306] Microcrystalline cellulose 410.0

[0307] Starch 50.0

[0308] Sodium starch glycolate 15.0

[0309] Magnesium stearate 5,0

[0310] 500.0

[0311] (iii) Capsule mg / capsule

[0312] 'Compound X' 10.0

[0313] Colloidal silicon dioxide 1.5

[0314] Lactose 465.5

[0315] Pregelatinized starch 120.0

[0316] Magnesium stearate 3,0

[0317] 600.0

[0318] (iv) Injection 1 (1 mg / mL) mg / mL

[0319] 'Compound X' (free acid form) 1.0

[0320] Dibasic sodium phosphate 12.0

[0321] Monobasic sodium phosphate 0.7

[0322] Sodium chloride 4.5

[0323] 1.0 N Sodium hydroxide solution q.s.

[0324] (pH adjustment to 7.0-7.5)

[0325] Water for injection q.s. ad 1 mL (v) Injection 2 (10 m&'mL) ma / mL

[0326] 'Compound X' (free acid form) 10.0

[0327] Monobasic sodium phosphate 0.3

[0328] Dibasic sodium phosphate 1.1

[0329] Polyethylene glycol 400 200.0

[0330] 0.1 N Sodium hydroxide solution q.s.

[0331] (pH adjustment to 7.0-7.5)

[0332] Water for injection q.s. ad 1 mL

[0333] (vi) Aerosol mg / can

[0334] 'Compound X' 20

[0335] Oleic acid 10

[0336] Trichloromonofluoromethane 5,000

[0337] Dichlorodifluoromethane 10,000

[0338] Dichlorotetrafluoroethane 5,000

[0339] (vii) Topical Gel 1 wt.%

[0340] 'Compound X' 5% Carbomer 934 1.25%

[0341] Triethanolamine q.s. (pH adjustment to 5-7) Methyl paraben 0.2% Purified water q.s. to 100g

[0342] (viiil Topical Gel 2 wt.%

[0343] 'Compound X' 5% Methylcellulose 2% Methyl paraben 0.2% Propyl paraben 0.02% Purified water q.s. to 100g

[0344] (ix) Topical Ointment wt.%

[0345] 'Compound X' 5%

[0346] Propylene glycol 1%

[0347] Anhydrous ointment base 40%

[0348] Polysorbate 80 2%

[0349] Methyl paraben 0.2%

[0350] Purified water q.s. to 100g

[0351] (xl Topical Cream 1 wt.%

[0352] 'Compound X' 5% White bees wax 10% Liquid paraffin 30% Benzyl alcohol 5% Purified water q.s. to 100g

[0353] (xi) Topical Cream 2 wt.%

[0354] 'Compound X' 5%

[0355] Stearic acid 10%

[0356] Glyceryl monostearate 3% Polyoxyethylene stearyl ether 3% Sorbitol 5%

[0357] Isopropyl palmitate 2 %

[0358] Methyl Paraben 0.2%

[0359] Purified water q.s. to 100g

[0360] These formulations may be prepared by conventional procedures well known in the pharmaceutical art. It will be appreciated that the above pharmaceutical compositions may be varied according to well-known pharmaceutical techniques to accommodate differing amounts and types of active ingredient 'Compound X'. Aerosol formulation (vi) may be used in conjunction with a standard, metered dose aerosol dispenser. Additionally, the specific ingredients and proportions are for illustrative purposes. Ingredients may be exchanged for suitable equivalents and proportions may be varied, according to the desired properties of the dosage form of interest.

[0361] All publications, patents, and patent documents cited herein are incorporated by reference as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, many variations and modifications may be made while remaining within the spirit and scope of the invention.

[0362] While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula I:whereinA is a direct bond, NH, O, -OP(=O)(OH)O-, or -(OCFbCE^pO- wherein p is 1-3; each R1is independently -(Ci-Ce)alkyl, -(C3-C6)cycloalkyl, -(C=O)(Ci-C6)alkyl, or H;R2is -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, -(C=O)(Ci-C6)alkyl, or H;R3is H, -(Ci-C6)alkyl, -(C3-C6)cycloalkyl, or -(C=O)(Ci-C6)alkyl;R4is nitrogen heterocycle, amino, guanidine, amino acid, or saccharide, each optionally substituted; or when A is NH, O, -OP(=O)(OH)O-, or -(OCH2CH2)PO-, R4is optionally H; and m is 1-8; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein each R1is independently methyl, ethyl, or acetyl.

3. The compound of claim 1, wherein R2is methyl, ethyl or acetyl.

4. The compound of claim 1, wherein R3is H.

5. The compound of claim 1, wherein R4is piperidine, piperazine, pyrrolidine, morpholine, alkylamine, aziridine, azetidine, hexose, or pentose; each optionally substituted.

6. The compound of claim 1, wherein m is 2, 3, 4, or 5.

7. The compound of claim 1, wherein R4is piperidin-4-yl, X-methylpiperidin-4-yl, N,N- dimethylamine, .X-methylamine, X-ethylamine, X-isobutylamine, XX-di ethylamine, JV-methyl-X- ethylamine, azetidine-l-yl, pyrrolidin-l-yl, X-methyl -pyrroli din-3 -yl, or hydroxy-pyrrolidin-l-yl.

8. The compound of claim 1, represented by Formula IIA or Formula IIB:whereinR4is amino, piperidine, piperazine, pyrrolidine, morpholine, guanidine, aziridine, or azetidine, each optionally substituted; and m is 3 or 4; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, represented by Formula IIC or Formula IID:whereinR4is amino, piperidine, piperazine, pyrrolidine, morpholine, guanidine, aziridine, or azetidine, each optionally substituted; and m is 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, represented by one of Formulas IIIA, IIIB, and IIIC:whereinR5is H or -(Ci-C6)alkyl;R6is H, -C=NR7(N(R7)2), or -(Ci-C6)alkyl; and each R7is independently H or -(Ci-Ce)alkyl; orR5and R6taken together with the nitrogen atom to which they are attached form a 3- membered, 4-membered, 5-membered, or 6-membered nitrogen heterocycle; or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, wherein R5and R6taken together with the nitrogen atom to which they are attached form pyrrolidin-l-yl or hydroxyl-substituted pyrrolidin-l-yl.

12. The compound of claim 1, wherein each -(Ci-Cg)alkyl is independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or hexyl.

13. The compound of claim 1, wherein the substituents at the 2-position and at the 3-position of the chromanone ring of Formulas I, IIA-D, or IIIA-C have a / ra / is-configuration.

14. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

15. A composition comprising a compound of any one of claims 1-14 and an excipient, one or more natural products, or both an excipient and one or more natural products.

16. The composition of claim 15, wherein composition comprises one or more natural products selected from ashwagandha extract, valerian extract, magnolia extract, jujube extract, lemon balm, L- theanine, melatonin, folic acid, and vitamin B.

17. A method for treating a subject in need of neuromodulation comprising: administering to the subject an effective amount of a compound according to any one of claims 1-14 to provide the neuromodulation; wherein optionally the neuromodulation effectively aids the treatment of Alzheimer’s disease, Parkinson’s disease, vascular dementia, Lewy body dementia, frontotemporal dementia, mixed dementia, Wernicke-Korsakoff syndrome, or a combination thereof.

18. The method of claim 17, wherein the neuromodulation effectively aids a pathological change in the subject, and the pathological changes comprises increased A0 and Tau, neuroinflammation, cognitive deficit, memory deficit, or a combination thereof.

19. The method of claim 17, wherein the neuromodulation effectively aids insomnia, sleep, a sleep disorder, anxiety, depression, aggression, cognition, memory, or a combination thereof.

20. The method of claim 17, wherein the neuromodulation effectively aids the treatment of post- traumatic stress disorder, autism, epilepsy, alcohol use disorder, fetal alcohol syndrome, addiction, cancer, or a combination thereof.

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