Use of phytocannabinoids and their analogs as negative allosteric modulators of the CB1 receptor

Abstract

In one aspect, the disclosure relates to the use of negative allosteric modulators (NAMs) of cannabinoid receptor 1 (CB1) and pharmaceutical compositions comprising the same in methods of treating or preventing diseases or disorders including substance abuse, anxiety, pain, obesity, cancers, neurodegenerative disorders, and central nervous system (CNS) disorders. In one aspect, the NAM can be selected from H4-CBD or CBDP. In some aspects, the pharmaceutical compositions additionally include Δ9-tetrahydrocannabinol (THC), and the NAMs of CB1 reduce or eliminate unwanted neurological side effects of THC while preserving its disease- and symptom-mitigating effects.

Description

USE OF PHYTOCANNABINOIDS AND THEIR ANALOGS AS NEGATIVE ALLOSTERIC MODULATORS OF THE CB1 RECEPTORCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 63 / 550,723, filed February 7, 2024, which is incorporated herein by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant number P30GM 122733- 01 A1 awarded by the National Institute of General Medical Sciences of the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] Cannabis (Cannabis sativa) consumption for medical and recreational purposes is a hotly debated social and political issue that has been increasing dramatically in the public eye within the last decade. Recently, the passage of the 2018 Farm Bill on industrial hemp (C. sativa with <0.3% tetrahydrocannabinol (THC)) and legalization of medicinal use of Cannabis sativa and its constituents in US states allowed consumers to readily access such materials for the management of pain and other medical symptoms, resulted in a proliferation of cannabis products (e.g., Dronabinol / Marinol™, Epidiolex). Cannabis contains more than 600 phytoconstituents; among them, -120 constituents are recognized as cannabinoids, and another 120+ compounds as terpenes. Many of these constituents are recognized to have deleterious and / or potential therapeutic effects, which are often mediated through the endogenous cannabinoid system.

[0004] Cannabinoid receptors are G-protein-coupled receptors (GPCRs), and approximately 35% of Food and Drug Administration-approved small molecules target GPCRs. Cannabinoid receptors are of two subtypes, CB1 and CB2. CB1 receptors are present in various brain parts and play important roles in rewards, learning, memory, motor control, and addiction. Chronic and acute use of cannabis strains and extracts containing high concentrations of A9-THC compared to cannabidiol (CBD) has been associated with numerous neuropsychiatric side effects, including anxiogenic effects, cognitive and memory impairment, and dependence.

[0005] Characterizing alternative and distinct allosteric binding sites on CB1 has led to the development of novel CB1- positive and negative allosteric modulators (PAMs and NAMs, respectively). The binding of a pure NAM to an allosteric site decreases the affinity and / or efficacyof signaling of the orthosteric or endogenous ligand at the orthosteric binding site. Crucially, a CB1-NAM, by reducing endogenous signaling in a spatially- and temporally-controlled fashion, may produce a more optimal spectrum of physiological effects than direct CB1 antagonism, resulting in a more desirable pharmacological profile.

[0006] Target selectivity and off-target side effects are the two major limiting factors for orthosteric CB1 ligands; therefore, the search for allosteric modulators (AMs) is a widely used drug discovery approach to avoid such limitations. Emerging clinical and preclinical findings demonstrate that CBD, the major non-psychoactive phytocannabinoid in Cannabis, possesses antipsychotic and anxiolytic properties, while the neuropsychiatric side effects of Cannabis are associated with THC. CBD is believed to mitigate the neuropsychiatric side effects of THC; however, the precise molecular mechanisms are largely unknown. Additionally, CBD has already been established to possess a poor binding affinity with CB1 and CB2 receptors, so researchers believe CBD analogs will unlikely bind more effectively with CB receptors.

[0007] However, phytocannabinoids and their analogs offer a potential advantage for developing precision drugs or formulations in combination with THC for many disorders involving CB1 receptors. Interestingly, recent studies have shown that CBD binds to the CB1 receptor as a negative allosteric modulator (NAM), and only a few synthetics (viz., ORG27569, PSNCBAM-1 , Fenofibrate, and ABM300) and endogenous ligand (viz., pregnenolone) are known to date; these are known to have poor efficacy. CB1 NAMs hold the potential to develop subtype-specific and pathway-specific therapeutics for the treatment of pain, anxiety, substance abuse, obesity, cancer, and neurodegenerative disorders, in combination with THC, and could serve as mitigators of THC-induced memory loss and cognitive function impairment.

[0008] Despite advances in cannabinoid analog research, there is still a scarcity of compounds that are both potent, efficacious, and selective negative allosteric modulators of CB1 and effective in mitigating negative side effects associated with THC as a potential anti-inflammatory agent. These needs and other needs are satisfied by the present disclosure.SUMMARY

[0009] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to the use of negative allosteric modulators (NAMs) of cannabinoid receptor 1 (CB1) and pharmaceutical compositions comprising the same in methods of treating or preventing diseases or disorders including substance abuse, anxiety, pain, obesity, cancers, neurodegenerative disorders, and central nervous system (CNS)diseases. In one aspect, the NAM can be selected from H4-CBD or CBDP with a pharmaceutically-acceptable carrier or diluent. In some aspects, the pharmaceutical compositions additionally include A9-tetrahydrocannabinol (THC), and the NAMs of CB1 reduce or eliminate unwanted neurological side effects of THC while preserving its disease- and symptom-mitigating effects.

[0010] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale, emphasis instead being placed upon clearly illustrating the principles of the present disclosure. Moreover, in the drawings, like reference numerals designate corresponding parts throughout the several views.

[0012] FIGs. 1 A-1 D show the in vitro activity of H4-CBD and CBDP. Corresponding analyses are provided in Tables 1 and 2. FIG. 1A shows both H4-CBD and CBDP are not agonists of CB1 compared to the full agonist CP55,940. FIGs. 1B-1C show that adding increasing concentrations of H4-CBD or CBDP results in a concentration-dependent decrease in the potency and efficacy of CB1 signaling by CP55,940 (an orthosteric agonist), consistent with negative allosteric modulation, in Chinese hamster ovary cells (CHO) stably-expressing human CB1. The binding affinity of H4-CBD and CBDP to CB1 was measured in membranes from CHO CB1 cells compared to the control compound CP55.940 (an orthosteric agonist) and CBD (a reference for comparison) (FIG 1 D). Mutagenesis of selected amino acids at CB1 receptor altered the competition binding of H4-CBD and CBDP compared to CBD or the orthosteric ligand CP55.940 in the presence of [3H]-SR141716A (FIG 1D). Specifically, the S401847AA mutation augmented H4-CBD binding similar to CBD; whereas F237446AA augmented H4-CBD binding andW241450AA abolished binding (FIG 1D). Likewise, for CBDP, the S401847AA mutation augmented binding similar to CBD; and W241450AA abolished binding, suggesting both CBDP and H4-CBD share similar modes of CB1 interaction (FIG 1 D).

[0013] FIG. 2 shows the neurobehavioral effects of A9-THC, H4-CBD, and their combination on locomotor activity upon intraperitoneal (I.P.) administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, H4-CBD (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, H4-CBD + A9-THC (10 +10 mg / kg, 1:1 w / w) groups were studied.

[0014] FIGs. 3A-3B show the neurobehavioral effects of A9-THC, H4-CBD, and their combination on (FIG. 3A) hot plate latency and (FIG. 3B) tail flick upon I.P. administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, H4-CBD (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, H4-CBD + A9-THC (10+10 mg / kg, 1 :1 w / w) groups were studied.

[0015] FIGs. 4A-4B show the neurobehavioral effects of A9-THC, H4-CBD, and their combination on (FIG. 4A) catalepsy and (FIG. 4B) body core temperature upon I.P. administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, H4-CBD (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, H4-CBD+ A9-THC (10+10 mg / kg, 1 :1 w / w) groups were studied.

[0016] FIG. 5 shows an interaction bar plot for the percentage of time with the novel object (learning and impairment effects) associated with a vehicle (blue), H4-CBD (orange), A9-THC (gray), and H4-CBD+ A9-THC combination (pattern-filled).

[0017] FIG. 6 shows the neurobehavioral effects of A9-THC, CBDP, and their combination on locomotor activity upon I.P. administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, CBDP (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, CBDP + A9-THC (10+10 mg / kg, 1 :1 w / w) groups were studied.

[0018] FIGs. 7A-7B show the neurobehavioral effects of A9-THC, CBDP, and their combination on (FIG. 7A) hot plate latency and (FIG. 7B) Tail flick upon I.P. administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, CBDP (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, CBDP + A9-THC (10+10 mg / kg, 1 :1 w / w) groups were studied.

[0019] FIGs. 8A-8B show the neurobehavioral effects of A9-THC, CBDP, and their combination on (FIG. 8A) catalepsy and (FIG. 8B) body core temperature upon I.P. administration to isogenic C57BL / 6NHsd mice. A total of four (i, vehicle; ii, CBDP (10 mg / kg); iii, A9-THC (10 mg / kg) and iv, CBDP+ A9-THC (10+10 mg / kg, 1:1 w / w) groups were studied.

[0020] FIG. 9 shows an interaction bar plot for the percentage of time with the novel object(learning and impairment effects) associated with a vehicle (blue), CBDP (orange), A9-THC (gray), and CBDP+ A9-THC combination (pattern-filled).

[0021] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.DETAILED DESCRIPTION

[0022] Disclosed herein is the use of structurally-related natural or synthetic cannabidiol (CBD) compounds such as cannabidiphorol (CBDP) and H4-CBD as negative allosteric modulators (NAMs) that have been tested as CBI-NAMs using an in vitro CB1 cAMP inhibition assay (FIGs 1A-1C). Binding was established related to the inverse agonist [3H]-SR141716A (FIG 1D). The binding site of these NAMs was putatively identified by site-directed mutagenesis experiments involving amino acids S401847AA of the intracellular site between TMHs 2, 6 and 7; or F237446AA and / or W241450AA at the TMH2 and TMH4 cholesterol binding motif (FIG 1D). The in vitro data indicated that the intracellular site (TMH2, TMH6, TMH7, and helix 8) was the most favorable and preferred allosteric site for H4-CBD and CBDP at CB1 R. This study also examined the effects of administering H4-CBD or CBDP intraperitoneally, in combination with A9-THC, on measures of locomotor activity, antinociceptive effects, body temperature, catalepsy (i.e. , cannabinoid tetrad), and learning and memory using novel object recognition test in male mice. In one aspect, in vivo testing confirmed that H4-CBD and CBDP mitigate A9-THC-induced memory impairment without altering the beneficial biological attributes of A9-THC. In one aspect, disclosed herein is the use of these CBD analogs in combination with A9-THC to treat obesity, drug abuse, pain and central nervous system (CNS) disorders.

[0023] In one aspect, disclosed herein is a pharmaceutical composition that includes a negative allosteric modulator (NAM) of cannabinoid receptor 1 (CB1), wherein the NAM comprises a compound of Formula I or a pharmaceutically acceptable ester, amide, salt, or prodrug thereof:Formula I wherein X is selected from H, OH, or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; wherein C1’-C2’ is dihydro or dehydro; wherein two of Ria, Rib, and Ricare OH, and wherein the Ria, R , or Ricthat is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by *** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof. provided that the NAM is not CBD or abnormal (abn)-CBD; and provided that when Riaand Ricare OH, R is not linear alkyl.

[0024] In some aspects, in the pharmaceutical compositions, R and Rw are OH and Riais selected from C1 -C9 linear or branched alkyl or cycloalkyl; 02-06 ether, ester, amide, or / V-alkyl amide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl. In other aspects, in the pharmaceutical compositions, Riaand Ricare OH and R is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkyl amide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl. In any of these aspects, the Ria, Rib, or Ricthat is not OH is:wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.

[0025] In one aspect, in the pharmaceutical compositions, the NAM is selected from

[0026] In another aspect, the NAM can be H4-CBD, CBDP, or any combination thereof.

[0027] In any of these aspects, the pharmaceutical compositions further include A9- tetrahydrocannabinol (A9-THC). In one aspect, in the pharmaceutical compositions, the NAM and the THC are present in a weight ratio of from about 1:0.13 to about 1 :1 , or of about 1 :0.13, 1 :0.3, or 1:1.

[0028] In one aspect, the pharmaceutical compositions can further include at least one carrier, diluent, or excipient, such as for example, a solvent, emulsifier, surfactant, or any combination thereof.

[0029] Also disclosed herein are methods for treating or preventing diseases or disorders in a subject, the method including at least the step of administering the disclosed pharmaceutical compositions to the subject by a route such as, for example, oral or parenteral administration. In one aspect, the NAM is administered in an amount of from about 10 mg / kg of the subject body weight to about 20 mg / kg of the subject body weight, or at about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg of the subject body weight, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values. In another aspect, the THC is administered in an amount of from about 1 mg / kg of subject body weight to about 20 mg / kg of subject body weight, or at about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg of subject body weight, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values.

[0030] In any of these aspects, the disease or disorder can be selected from obesity, substance abuse, pain, anxiety, cancer, a neurodegenerative disorder, or another central nervous system (CNS) disorder. In one aspect, the cancer can be selected from acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, astrocytoma, basal cell carcinoma, bladder cancer, breast cancer, Burkitt’s lymphoma, carcinoid tumor, cervical cancer,chondroblastoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, cutaneous t-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, extrahepatic bile duct cancer, gallbladder cancer, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi’s sarcoma, laryngeal cancer, lip and oral cavity cancer, liver cancer, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thymoma, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom’s macroglobulinemia, Wilms’ tumor, or any combination thereof. In another aspect, the neurodegenerative disorder can be selected from Alzheimer’s disease, amyotrophic lateral sclerosis, Friedrich ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, spinal muscular atrophy, or any combination thereof. In still another aspect, the CNS disorder can be selected from encephalitis, meningitis, stroke, multiple sclerosis, arachnoid cysts, attention deficit / hyperactivity disorder, autism, catalepsy, epilepsy, infection, migraine, myelopathy, Tourette’s, or any combination thereof.

[0031] In one aspect, the use of the NAM reduces or eliminates one or more side effects of the THC such as, for example, altered senses, mood changes, impaired body movement, cognitive impairment, or any combination thereof. In another aspect, although the NAM reduces or eliminates side effects, the NAM does not compete with or minimize the beneficial effects of THC derived by the subject from using the pharmaceutical compositions.

[0032] In one aspect, the subject can be a mammal such as, for example, a human, cat, dog, goat, sheep, cattle, horse, swine, hamster, guinea pig, rat, rabbit, or mouse.

[0033] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, benefiting from the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of theappended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0034] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0035] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0036] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated; it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to the arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0037] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0038] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0039] It is also to be understood that the terminology used herein describes particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0040] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.Definitions

[0041] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.”

[0042] “Dehydro” as used herein refers to a bond, such as a bond between two carbon atoms, wherein each carbon has lost at least one hydrogen atom. A “dihydro” carbon-carbon bond, meanwhile, has one more hydrogen atom per carbon in the bond and a lower bond order than the same bond in a dehydro state.

[0043] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a subject,” “a behavioral assay,” or “an excipient,” include, but are not limited to, mixtures, combinations, or groups of two or more such subjects, behavioral assays, or excipients, and the like, as appropriate.

[0044] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. 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. It is also understood that there are a number of values disclosed herein, and that eachvalue is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0045] When a range is expressed, a further aspect includes from the one particular value and / or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0046] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or subranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0047] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, thevalue that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0048] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material. For example, an “effective amount” of a negative allosteric modulator (NAM) refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired level of modulation of CB1 receptor activity and / or modulation of binding of CB1 ligands. The specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the amount and type of NAM, amount and type of other ligands present, patient age, sex, and body weight, and condition being treated.

[0049] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0050] As used herein, “administering” can refer to an administration that is oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra-joint, parenteral, intra-arteriole, intradermal, intraventricular, intraosseous, intraocular, intracranial, intraperitoneal, intralesional, intranasal, intracardiac, intraarticular, intracavernous, intrathecal, intravireal, intracerebral, and intracerebroventricular, intratympanic, intracochlear, rectal, vaginal, by inhalation, by catheters, stents or via an implanted reservoir or other device that administers, either actively or passively (e.g. by diffusion) a composition the perivascular space and adventitia. For example a medical device such as a stent can contain a composition or formulation disposed on its surface, which can then dissolve or be otherwise distributed to the surrounding tissue and cells. The term “parenteral” can include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophylactically; thatis, administered for prevention of a disease or condition.

[0051] As used herein, “therapeutic agent” can refer to any substance, compound, molecule, and the like, which can be biologically active or otherwise can induce a pharmacologic, immunogenic, biologic and / or physiologic effect on a subject to which it is administered to by local and / or systemic action. A therapeutic agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. A therapeutic agent can be a secondary therapeutic agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed. The term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14th edition), the Physicians' Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition), and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double-and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or prodrugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0052] As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g. human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to human and constituents thereof.

[0053] As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and / or physiological effect. The effect can be, but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom or condition thereof, such as pain, substance abuse, and / or cancer The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of pain, substance abuse, and / or cancer in a subject, particularly a human and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. The term "treatment" as used herein can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and / or those in which the disorder is to be prevented. As used herein, the term "treating", can include inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and / or condition. T reating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0054] As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and / or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.

[0055] As used herein, “therapeutic” can refer to treating, healing, and / or ameliorating a disease, disorder, condition, or side effect, or to decreasing in the rate of advancement of a disease, disorder, condition, or side effect.

[0056] As used herein, “effective amount” can refer to the amount of a disclosed compound or pharmaceutical composition provided herein that is sufficient to effect beneficial or desired biological, emotional, medical, or clinical response of a cell, tissue, system, animal, or human. An effective amount can be administered in one or more administrations, applications, or dosages. The term can also include within its scope amounts effective to enhance or restore to substantially normal physiological function.

[0057] As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.

[0058] For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multipledoses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

[0059] A response to a therapeutically effective dose of a disclosed compound and / or pharmaceutical composition, for example, can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and / or pharmaceutical composition, by changing the disclosed compound and / or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.

[0060] As used herein, the term “prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.

[0061] As used herein, the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0062] The term “pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0063] The term “pharmaceutically acceptable salts”, as used herein, means salts of the active principal agents which are prepared with acids or bases that are tolerated by a biological system or tolerated by a subject or tolerated by a biological system and tolerated by a subject when administered in a therapeutically effective amount. When compounds of the present disclosurecontain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include, but are not limited to; sodium, potassium, calcium, ammonium, organic amino, magnesium salt, lithium salt, strontium salt or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to; those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively non-toxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.

[0064] The term “pharmaceutically acceptable ester” refers to esters of compounds of the present disclosure which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Examples of pharmaceutically acceptable, nontoxic esters of the present disclosure include C 1 -to-C 6 alkyl esters and C 5 -to-C 7 cycloalkyl esters, although C 1 -to-C 4 alkyl esters are preferred. Esters of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable esters can be appended onto hydroxy groups by reaction of the compound that contains the hydroxy group with acid and an alkylcarboxylic acid such as acetic acid, or with acid and an arylcarboxylic acid such as benzoic acid. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable esters are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine and an alkyl halide, for example with methyl iodide, benzyl iodide, cyclopentyl iodide or alkyl triflate. They also can be prepared by reaction of the compound with an acid such as hydrochloric acid and an alcohol such as ethanol or methanol.

[0065] The term “pharmaceutically acceptable amide” refers to nontoxic amides of the present disclosure derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6- membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C3 alkyl primary amides and C 1 -to-C 2 dialkyl secondary amides are preferred. Amides of disclosed compounds can be prepared according to conventional methods. Pharmaceutically acceptable amides can be prepared from compounds containing primary or secondary amine groups by reaction of the compound that contains the amino group with an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide. In the case of compounds containing carboxylic acid groups, the pharmaceutically acceptable amides are prepared from compounds containing the carboxylic acid groups by reaction of the compound with base such as triethylamine, a dehydrating agent such as dicyclohexyl carbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine, for example with methylamine, diethylamine, and piperidine. They also can be prepared by reaction of the compound with an acid such as sulfuric acid and an alkylcarboxylic acid such as acetic acid or with acid and an arylcarboxylic acid such as benzoic acid under dehydrating conditions such as with molecular sieves added. The composition can contain a compound of the present disclosure in the form of a pharmaceutically acceptable prodrug.

[0066] The term “pharmaceutically acceptable prodrug” or “prodrug” represents those prodrugs of the compounds of the present disclosure which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Prodrugs of the present disclosure can be rapidly transformed upon in vivo administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield a parent compound of the present invention having a structure of a disclosed compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the ACS Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987).

[0067] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0068] The present invention also includes isotopically-labeled compounds, which are identical to the compounds disclosed herein, but for the fact that one or more atoms can be replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into a compound disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,170,180 ,32P,35S,18F, and36CI, respectively.

[0069] In various aspects, the disclosed compounds can possess at least one center of asymmetry, they can be present in the form of their racemates, in the form of the pure enantiomers and / or diastereomers or in the form of mixtures of these enantiomers and / or diastereomers. The stereoisomers can be present in the mixtures in any arbitrary proportions. In some aspects, provided this is possible, the disclosed compounds can be present in the form of the tautomers.

[0070] Thus, methods which are known per se can be used, for example, to separate the disclosed compounds which possess one or more chiral centers and occur as racemates into their optical isomers, i.e., enantiomers or diastereomers. The separation can be effected by means of column separation on chiral phases or by means of recrystallization from an optically active solvent or using an optically active acid or base or by means of derivatizing with an optically active reagent, such as an optically active alcohol, and subsequently cleaving off the residue.

[0071] In a further aspect, the disclosed compounds can be isolated as solvates and, in particular, as hydrates of a disclosed compound, which can be obtained, for example, by crystallization from a solvent or from an aqueous solution. In this connection, one, two, three or any arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.

[0072] The disclosed compounds can be used in the form of salts derived from inorganic or organic acids. Pharmaceutically acceptable salts include salts of acidic or basic groups present in the disclosed compounds. Suitable pharmaceutically acceptable salts include base addition salts, including alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts, which may be similarly prepared by reacting the drug compound with a suitable pharmaceutically acceptable base. The salts can be prepared in situ during the final isolation and purification of the compounds of the present disclosure; or following final isolation by reacting a free base function, such as a secondary or tertiary amine, of a disclosed compound with a suitable inorganic or organic acid; or reacting a free acid function, such as a carboxylic acid, of a disclosedcompound with a suitable inorganic or organic base.

[0073] Acidic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting moieties comprising one or more nitrogen groups with a suitable acid. In various aspects, acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. In a further aspect, salts further include, but are not limited, to the following: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, 2-hydroxyethanesulfonate (isethionate), nicotinate, 2- naphthalenesulfonate, oxalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, undecanoate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Also, basic nitrogencontaining groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others.

[0074] Basic addition salts can be prepared in situ during the final isolation and purification of a disclosed compound, or separately by reacting carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutical acceptable metal cation or with ammonia, or an organic primary, secondary or tertiary amine. Pharmaceutical acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. In further aspects, bases which may be used in the preparation of pharmaceutically acceptable salts include the following: ammonia, L- arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine,diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.Pharmaceutical Compositions

[0075] In various aspects, the present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof. As used herein, “pharmaceutically-acceptable carriers” means one or more of a pharmaceutically acceptable diluents, preservatives, antioxidants, solubilizers, emulsifiers, coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, and adjuvants. The disclosed pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy and pharmaceutical sciences.

[0076] In a further aspect, the disclosed pharmaceutical compositions comprise a therapeutically effective amount of at least one disclosed compound, at least one product of a disclosed method, or a pharmaceutically acceptable salt thereof as an active ingredient, a pharmaceutically acceptable carrier, optionally one or more other therapeutic agent, and optionally one or more adjuvant. The disclosed pharmaceutical compositions include those suitable for oral, rectal, topical, pulmonary, nasal, and parenteral administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. In a further aspect, the disclosed pharmaceutical composition can be formulated to allow administration orally, nasally, via inhalation, parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intracranially and intratumorally.

[0077] As used herein, “parenteral administration” includes administration by bolus injection or infusion, as well as administration by intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[0078] In various aspects, the present disclosure also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a disclosed compound, a product of a disclosed method ofmaking, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof. In a further aspect, a disclosed compound, a product of a disclosed method of making, a pharmaceutically acceptable salt, a hydrate thereof, a solvate thereof, a polymorph thereof, or a stereochemically isomeric form thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.

[0079] Pharmaceutically acceptable salts can be prepared from pharmaceutically acceptable non-toxic bases or acids. For therapeutic use, salts of the disclosed compounds are those wherein the counter ion is pharmaceutically acceptable. However, salts of acids and bases which are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are contemplated by the present disclosure. Pharmaceutically acceptable acid and base addition salts are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the disclosed compounds are able to form.

[0080] In various aspects, a disclosed compound comprising an acidic group or moiety, e.g., a carboxylic acid group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic base. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free acid compound by treatment with an acidic reagent, and subsequently convert the free acid to a pharmaceutically acceptable base addition salt. These base addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.

[0081] Bases which can be used to prepare the pharmaceutically acceptable base-addition salts of the base compounds are those which can form non-toxic base-addition salts, i.e., salts containing pharmacologically acceptable cations such as, alkali metal cations (e.g., lithium, potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N-methylglucamine-(meglumine), loweralkanolammonium and other such bases of organic amines. In a further aspect, derived from pharmaceutically acceptable organic, non-toxic bases include primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. In various aspects, such pharmaceutically acceptable organic non-toxic bases include, but are not limited to, ammonia, methylamine, ethylamine, propylamine, isopropylamine, any of the four butylamine isomers, betaine, caffeine, choline, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, / .A / 1- dibenzylethylenediamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tromethamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, A / -methyl-D-glucamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, hydrabamine salts, and salts with amino acids such as, for example, histidine, arginine, lysine and the like. The foregoing salt forms can be converted by treatment with acid back into the free acid form.

[0082] In various aspects, a disclosed compound comprising a protonatable group or moiety, e.g., an amino group, can be used to prepare a pharmaceutically acceptable salt. For example, such a disclosed compound may comprise an isolation step comprising treatment with a suitable inorganic or organic acid. In some cases, it may be desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with a basic reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. These acid addition salts can be readily prepared using conventional techniques, e.g., by treating the corresponding basic compounds with an aqueous solution containing the desired pharmacologically acceptable anions and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they also can be prepared by treating the free base form of the disclosed compound with a suitable pharmaceutically acceptable non-toxic inorganic or organic acid.

[0083] Acids that can be used to prepare the pharmaceutically acceptable acid-addition salts of the base compounds are those which can form non-toxic acid-addition salts, i.e., salts containing pharmacologically acceptable anions formed from their corresponding inorganic and organic acids. Exemplary, but non-limiting, inorganic acids include hydrochloric hydrobromic, sulfuric, nitric, phosphoric and the like. Exemplary, but non-limiting, organic acids include acetic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, isethionic, lactic, maleic, malic, mandelicmethanesulfonic, mucic, pamoic, pantothenic, succinic, tartaric, p-toluenesulfonic acid and the like. In a further aspect, the acid-addition salt comprises an anion formed from hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

[0084] In practice, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present disclosure can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the present disclosure, and / or pharmaceutically acceptable salt(s) thereof, can also be administered by controlled release means and / or delivery devices. The compositions can be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

[0085] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The term “unit dosage form,” as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. That is, a “unit dosage form” is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets (including scored or coated tablets), capsules or pills for oral administration; single dose vials for injectable solutions or suspension; suppositories for rectal administration; powder packets; wafers; and segregated multiples thereof. This list of unitdosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

[0086] The pharmaceutical compositions disclosed herein comprise a compound of the present disclosure (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents. In various aspects, the disclosed pharmaceutical compositions can include a pharmaceutically acceptable carrier and a disclosed compound, or a pharmaceutically acceptable salt thereof. In a further aspect, a disclosed compound, or pharmaceutically acceptable salt thereof, can also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0087] Techniques and compositions for making dosage forms useful for materials and methods described herein are described, for example, in the following references: Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences Vol 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Vol 61 (Alain Rolland, Ed., 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Vol 40 (Gilbert S. Banker, Christopher T. Rhodes, Eds.).

[0088] The compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intendedform of administration and as consistent with conventional pharmaceutical practices. The deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration. Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used. The compounds may be administered as a dosage that has a known quantity of the compound.

[0089] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

[0090] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure.EXAMPLES

[0091] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, the temperature in °C or ambient temperature, and pressure at or near atmospheric pressure.Example 1 : Materials and Methods

[0092] CBD was obtained by isolating from Cannabis, fiber type, and its purity (>98%) was established using GC / MS and HPLC.Chemistry

[0093] All the chemicals and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) or Fisher Scientific USA. All reactions were carried out under an inert atmosphere (N2). The reactions were monitored by thin-layer chromatography (TLC) using precoated silica gel 60 F254 (MerckKGaA). TLC chromatograms were visualized under UV light at 254 and 366 nm and by using 5% H2SO4_MeOH as a spray reagent. The optical rotation was measured on an Autopol II,Automatic polarimeter (Rudolph Research Analytical) with a sodium lamp (589 nm) using a 10 mm cell length. The NMR spectra were recorded on Bruker model AMX NMR spectrometers at 400 or 500 MHz (1H) using deuterated solvents CDCh or DMSO-d6. Chemical shifts were referenced to the solvent peaks for CHCI3 at 6 H 7.26. The high-resolution mass spectrum (negative mode) was obtained on a JEOL AccuTOF DART 4G, a high-resolution atmospheric pressure ionization, time-of-flight mass spectrometer (HRAPITOFMS) coupled with direct analysis in real-time (DART).Preparation of (-)-1 ,2,8,9-tetrahydro-CBD (H4-CBD)

[0094] In a round bottom flask (50 mL) charged with a magnet bar, cannabidiol was introduced (100 mg, 0.318 mmol, 1.0 equiv.) and dissolved in EtOAc (4 mL), followed by the addition of platinum oxide (Adam's catalyst) (11.66 mg, 5.09 mmol, 0.16 equiv). In the next step, hydrogen gas was purged into the reaction mixture for one min and stirred under a hydrogen atmosphere for 90 min. After this time, TLC analysis showed the complete disappearance of the starting material. The reaction mixture was filtered from a 0.22 Millipore filter, and the solvent was evaporated to afford H4-CBD as a resinous matter (100 mg, 0.318 mmol, 98.7%), HPLC purity 100%.

[0095] 1H NMR (400 MHz, Chloroform-d) 5 6.20 (d, J = 1.6 Hz, 1 H), 6.14 (d, J = 1.6 Hz, 1 H), 5.37 (s, 1 H), 5.14 (s, 1 H), 3.04 (td, J = 11.3, 4.1 Hz, 1 H), 2.43 (dd, J = 9.0, 6.7 Hz, 2H), 2.07 (tt, J = 11.4, 2.8 Hz, 1 H), 1.78 - 1.50 (m, 8H), 1.33 (qd, J = 6.5, 5.9, 2.9 Hz, 4H), 1.17 - 1.01 (m, 2H), 0.90 (d, J = 6.1 Hz, 6H), 0.87 (t, J = 6.8 Hz, 3H), 0.74 (d, J = 6.9 Hz, 3H); [a]21D = -5.66 (c 0.150, MeOH); HRAPITOFMS calcd. for C2iH34O2[M-H]+317.2481 ; found 317.2464.Preparation of (-)-CBDP ((T ,2'F?)-4-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-T,2',3',4'-tetrahydro- [1 ,1'-biphenyl1-2,6-diol)

[0096] Pentafluorobenzeneboronic (PFBA) acid was added to a vigorously stirred ice-cold solution of (1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol and 5-heptyl resorcinol in a mixture of dichloromethane and hexafluoroisopropanol and stirred at the same temperature for 24 h. After completion of the reaction, the cooling bath was removed, and the solvent was evaporated to dryness using a rotary evaporator. The residue was adsorbed on celite and purified by flash column chromatography using 2-7% ethyl acetate in hexanes to get the desired compound in 61% yield.

[0097] 1H NMR (500 MHz, DMSO) 5 8.64 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1 H), 4.48 (d, J = 2.8 Hz, 1 H), 4.44 - 4.36 (m, 1H), 3.82 (ddd, J = 10.5, 4.2, 2.2 Hz, 1 H), 3.02 (ddd, J = 13.1 , 10.5, 2.8 Hz, 1 H), 2.29 (t, J = 7.6 Hz, 2H), 2.16 - 2.00 (m, 1 H), 1.91 (dd, J = 16.9, 5.0 Hz, 1 H), 1.72 - 1.65 (m, 1 H), 1.65 - 1.54 (m, 7H), 1.51 - 1.40 (m, 2H), 1.30 - 1.21 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H). 13C NMR (126 MHz, DMSO) 6 156.2, 149.1 , 140.2, 130.0, 126.9, 114.1 , 109.7, 106.6, 43.7, 35.5, 34.9, 31.3, 30.6, 30.3, 29.5, 28.7, 28.6, 23.3, 22.1 , 19.3, 14.0. HRMS (ESI) m / z calcd for C23H35O2 [M + H]+, 343.2637, found 343.2636.In vitro studies

[0098] CP55.940 (Cat. No. # 13608), was purchased from Cayman Chemical (Ann Arbor, Michigan 48108 USA) and stored at -20 °C. H4-CBD and CBDP were provided by investigators at the University of Mississippi to investigators at the University of Saskatchewan. Investigators at the University of Saskatchewan received coded compounds were blinded to compound identity. Unless specifically noted, all other materials (ethanol, DMSO, and phosphate-buffered saline, etc.) were from Sigma-Aldrich (Mississauga, ON). DMSO was added directly to the media at the indicated concentrations and times indicated, with a final concentration of 0.1% in assay media to dissolve the compounds. DMSO 0.1% was used as the vehicle control for all experiments.Cell Culture

[0099] Chinese hamster ovary (CHO)-K1 cells expressing human CB1 (hCB1) were used in this experiment. The cells were maintained at 37 °C and 5% CO2 in F-12 DMEM containing 1 mM L- glutamine, 1 % penicillin-streptomycin, hygromycin B (300 pg / mL), and G418 (600 pg / mL) and 10% FBS. HitHunter (cAMP) CHO-K1 cells stably expressing hCB1 from DiscoveRx® (Eurofins, Fremont, CA) were maintained at 37 °C and 5% CO2 in F-12 DMEM containing 10% FBS and 1% penicillin-streptomycin with 800 pg / mL geneticin.HitHunter cAMP Assay

[0100] CHO-K1 hCB1 cells were used to determine the inhibition of forskolin (FSK)-stimulated cAMP. Low-volume 384-well plates containing Opti-MEM containing 1% FBS at 37 °C and 5% CO2 incubated overnight were used to cultivate 5,000 CHO-K1 hCB1 cells / well. Then, Opti-MEM was discarded and replaced by the cell assay buffer (DiscoveRx). The cells were simultaneously treated with the compounds and 10 pM FSK for 90 min at 37 °C. Later, cAMP antibody and working detection solutions were added according to the manufacturer’s directions (DiscoveRx), and an additional 60-min incubation was done at room temperature. The DiscoveRx cAMPsolution A was added, and further incubation was done for 60 minutes at room temperature. Next, chemiluminescence was measured on a Cytation5 plate reader (top read, gain 200, integration time 10,000 ms).[3H1SR141716A Radioligand Competition Binding and Site-Directed Mutagenesis

[0101] Plasmids used for these experiments were synthesized and seguenced by GenScript (Piscataway, NJ) and have been described previously. Site-directed mutagenesis to produce the variants F237446AA, W241450AA, and S401847AA was performed by GenScript. Receptor plasmids were introduced into CHO-K1 cells using the Lipofectamine 3000 transfection reagent, according to the manufacturer’s instructions (Invitrogen, ThermoFisher Scientific, Waltham, MA). Cells were grown to ~80% confluency in 15 cm tissue culture plates in F-12 / DMEM containing 1 mM L-glutamine, 10% FBS, 1% Pen / Strep at 37 °C under 5% CO2. The cell media was aspirated, and cells were washed with 2 mL 1* phosphate-buffered saline (PBS). Cells were then incubated in serum-free media for 30 min at 37 °C. Lipofectamine 3000 solution was prepared by diluting Lipofectamine 3000 reagent in Opti-MEM. Plasmid solution was prepared by diluting plasmid DNA in Opti-MEM and P3000 reagent. Diluted Lipofectamine 3000 reagent was then added to the diluted plasmid solution, and the resultant solution was incubated for 15 min at room temperature. Following this, the Lipofectamine plasmid solution was added to the cells and cells were incubated for 48 h at 37 °C under 5% CO2prior to membrane collection (described below). Cells were transfected with 0.50 pg plasmid per plate. Radioligand binding assays were performed as described in previous work. Assays used 1 nM [3H]-SR141716A and Tris binding buffer (50 mM Tris-HCI, 50 mM Tris-base, 0.1% BSA, pH 7.4), in a total assay volume of 500 pL. Binding was initiated by the addition of transfected / ?CB1 CHO cell membranes (25 pg protein per well). All assays were performed at 37°C for 120 min prior to guenching with ice-cold Tris binding buffer followed by vacuum filtration using a 12-well sampling manifold (Brandel, Inc., Gaithersburg, MD, USA) and Brandel GF / B filters. Each reaction well was washed three times with 1 mL aliquots of T ris-binding buffer. The filters were air-dried overnight and then placed in 5 mL of scintillation fluid (Ultima Gold XR, Perkin Elmer, Inc., Waltham, MA, USA). Liquid scintillation spectrometry was used for quantifying radioactivity.Statistics

[0102] Data from HitHunter cAMP assays were represented as the percentage of CP55,940 response. Non-linear regression (three parameters) was used to fit concentration-response curves in GraphPad and Prism v9.0 to estimate potency and efficacy (Table 1). Data from theradioligand competition binding assays were represented as %[3H]-SR141716A bound and fit to a one-site-fit Ki model with both [3H]-SR141716A Kdand concentration constrained to 1 nM. Data are described as mean ± standard error of the mean (S.E.M.). For radioligand binding data, statistical analyses of pK, used two-way ANOVA followed by Tukey’s post-hoc test. P<0.05 was considered significant. Group sizes n = 5-20 (FIGs. 1A-1C) and n = 3-12 (FIG. 1D). See also Tables 1 and 2.In vivo studies

[0103] All procedures were preapproved by the Institutional Animal Care and Use Committee (IACUC) at the University of Mississippi. Experiments were carried out in accordance with ethical guidelines defined by the National Institutes of Health (NIH Publication No. 85-23).Chemical Solutions

[0104] H4-CBD and CBDP were synthesized as described above and diluted to a range of concentrations in a vehicle composed of ethyl alcohol, cremophor, and sterile saline in the ratio 1 :1 :8, volume / volume.Subjects and Housing

[0105] Experiments were performed using eight-week-old male C57BL / 6NHsd mice (Envigo, USA). Mice were housed in five groups with a 12 h light / 12 h dark cycle, and food and water were provided ad libitum. Treatment groups were randomized. Procedures involving animals were performed according to the guidelines approved by the Institutional Animal Care and Use Committee of the University of Mississippi and according to the National Institutes of Health Guide for Care and Use of Laboratory Animals [Application No.: 22-003],Behavioral Assays

[0106] Thirty minutes prior to baseline testing, mice were acclimated to the testing room. Preinjection baseline catalepsy bar, hot plate, tail-flick latency times, and core body temperature were recorded. Mice were injected intraperitoneally (i.p.) with the test compound, followed by THC injection at a 15-minute interval.Open Field Test (Total Horizontal Beam Breaks)

[0107] Immediately after THC treatment, animals were individually placed in activity chambers (San Diego Instruments, CA, USA), where the animals underwent a 15-minute acclimation period followed by a 30-minute testing period for locomotor activity. Total activity was expressed as thenumber of horizontal beam breaks during the 30-minute testing period. Each mouse then had its forepaws placed on a raised bar (4 cm in height), and their latency to either withdraw forepaws from the bar or climb onto the bar was recorded to the nearest second. Mice were removed from the bar after 30 seconds if no response was observed.Hot Plate and Tail Flick

[0108] For the hot plate assay, mice were placed on a hot plate (I ITC Life Science, CA, USA) twice with 30-second rest intervals, and the latency to flutter or lick hind paws or perform an escape response was recorded. If no attempt at these measures was made, animals were removed from the hot plate after 45 seconds. For the tail-flick assay, mice were lightly restrained and placed on a tail-flick analgesia meter (I ITC Life Science, CA, USA) twice with 20-second resting intervals and were exposed to radiate heat. The latency to flick tail was recorded. If no attempt at any of these measures was made, the animals were removed from the tail-flick meter after 10 seconds.Catalepsy and Core Body Temperature

[0109] Each mouse had forepaws placed on a raised bar (4 cm in height) for the catalepsy bar test, and their latency to either withdraw forepaws from the bar or climb onto the bar was recorded to the nearest second. Mice were removed from the bar after 30 seconds if no response was observed. Core body temperature was recorded by inserting a rectal probe with a connected thermocouple thermometer (Cole-Parmer, Clifton, IL, USA) to an approximate depth of 2 cm.Novel Object Recognition

[0110] Thirty minutes prior to the training phase, mice were acclimated to the testing room. For the training phase, each mouse was placed in an open field with two identical objects (Stoelting, IL, USA) approximately five centimeters apart. Mice were given ten minutes to explore the objects. Mice were returned to the home cage and given a 4-hour inter-trial interval (ITI). After the four hours (ITI), one of the identical objects was replaced with a novel object, and mice were given ten minutes to explore the objects. The length of time exploring each object in both the training and testing phases was recorded.Statistical Analyses

[0111] Statistical analyses were performed using StatView (SAS Institute Inc., Cary, NC, USA). All values are presented as mean ± SEM with n = 8-12 animals / group. Analgesia in the hot plate assay was expressed as the percent maximal possible effect [% MPE = (post drug latency - basallatency) I (45 sec - basal latency) x 100], Antinociception in the tail flick assay was expressed as the percent maximal possible effect [% MPE = (post drug latency - basal latency) I (10 sec - basal latency) x 100]. Novel object recognition was expressed as the proportion of time spent with the novel object as a function of all the time spent exploring [% time with novel object = time with novel object / (time with familiar object + time with novel object) x 100]. Measures that are dependent on the tetrad, hot plate, and tail flick assays were analyzed by two-way analyses of variance (ANOVA) with pretreatment condition and THC condition as factors. Novel object recognition data were analyzed via repeated measures ANOVA with pretreatment condition and THC condition as between-subject’s factors and trial (training or testing trial) as the within-subjects factor. Group differences following main effects were determined via Fisher's Protected Least Significant Difference (PLSD) post-hoc tests. Interactions were delineated via simple main effects, and the main effect contrasts with alpha corrected for family-wise error. All effects were considered significant when p < 0.05.Example 2: ResultsSynthesis of H4-CBDCBD H4-CBDScheme 1

[0112] H4-CBD was prepared as described previously (Ben-Shabat, Hanus, Katzavian, & Gallily, 2006; Scheme 1). Full hydrogenation of (-)-CBD was carried out using PtO2 as a catalyst and stirred under a hydrogen atmosphere for 90 minutes. The stereochemical orientation of methyl at C1 was assigned as a based on the detection of correlations in the NOESY spectrum between H-3 (5 3.04, td, J = 11.3, 4.1 Hz) and Me-7 (5 0.74, d, J = 6.9Hz).Synthesis of CBDP61 %CBDPScheme 2

[0113] Synthesis of CBDP was accomplished as described above and as shown in Scheme 2.Inhibition of cAMP

[0114] CHO cells stably-expressing CB1 were treated with 0.1 nM - 10 pM CP55,940, H4-CBD, or CBDP; or CP55.940 and 1 nM, 100 nM, or 10 pM of H4-CBD or CBDP and the inhibition of forskolin-stimulated cAMP accumulation was measured in the HitHunter assay (FIGs. 1A-1C) (Table 1). H4-CBD and CBDP produced a small degree of agonism (27% and 32%, respectively) at the highest concentration tested (FIG. 1A) H4-CBD and CBDP both produced concentrationdependent decreases in potency (as indicated by the rightward shift of the concentrationresponse curve and decreasing pEC5o values) and efficacy (as indicated by the downward shift of the concentration-response curve and decreasing Emaxvalues) (FIGs. 1B-1C, Table 1). These observations with H4-CBD and CBDP are consistent with previously published literature and the notion that these compounds behave as CB1 NAMs (FIGs. 1 B-1C).Radioligand binding

[0115] H4-CBD and CBDP displayed moderate affinity for wild-type CB1 (33 nM and 65 nM, respectively) (Table 2); compared to the CB1 agonist CP55.940 (2.1 nM). The reference compound, CBD, displayed a much lower affinity (380 nM) than previously reported (FIG. 1D).Mutagenesis of S401847AA at the intracellular site between transmembrane helices (TMHs) 2, 6 and 7 augmented H4-CBD binding (p=0.71) similarly to CBD; whereas at the TMH2 and TMH4 cholesterol binding motif, F237446AA augmented H4-CBD binding and W241450AA eliminated binding, suggesting that H4-CBD can interact not only with the same site as CBD but also with other CB1 residues (FIG. 1D). For CBDP, the mutagenesis of S401847AA at the TMHs 2, 6 and 7 site augmented binding similarly to CBD. At the TMH2 and 4 site (cholesterol binding motif site), W241450AA abolished CBDP binding, indicating CB1 interaction similarities for both CBDP and H4-CBD (FIG. 1D).T etrad Assay

[0116] The tetrad assay is a series of behavioral tests that exemplifies the pharmacological effects of cannabinoids. THC has been shown to produce decreases in spontaneous activity, catalepsy, hypothermia, and antinociception. In the current study, the open field data was collected 15 minutes post-THC administration and run for an additional 15 minutes (a total of 30 min). Data were collected after the 30 minute in the open field, approximately 45 to 55 minutes from post-THC administration, for catalepsy, hot plate, tail-flick, and body temperature measurements.Behavioral Tests and Novel Object Recognition Test for H4-CBD

[0117] Open Field (Total Horizontal Beam Breaks). The combination of H4-CBD and THC administration significantly influenced the total locomotion in an open field [F(1 ,28)=12.04, p < 0.05] compared to THC alone (p < 0.0001). H4-CBD similarly decreased locomotion (p < 0.0001) but did not significantly modify THC's effects (however, this may have been due to a 'floor effect' since THC had already depressed motor behavior greatly) (FIG. 2).

[0118] Hot Plate and Tail Flick Observations. The combination of H4-CBD and THC administration significantly interacted to influence the latency to paw withdrawal on the hot plate test [F(1 ,28)=4.39, p < 0.05] and showed significant antinociception. As shown in FIGs. 3A-3B,THC significantly increased the latency to withdrawal (p = 0.004), and in combination with H4- CBD, it exerted additive effects to further increase the latency to withdrawal (p = 0.03) (FIG. 3A). THC's significant antinociception was also indicated by an increase in the maximum possible effect (%MPE) of tail withdrawal in response to a radiant heat stimulus [F(1 ,28)=14.24, p < 0.05] when given in combination with H4-CBD. In contrast, no additional effect of the H4-CBD alone was observed (FIG. 3B).

[0119] Catalepsy and Core Body Temperature. A combination of THC and H4-CBD significantly increased catalepsy was indicated by increased latency to paw withdrawal from an elevated bar stand [F(1 ,28)=9.28, p < 0.05] compared to A9-THC alone . However, alone H4-CBD's effect on catalepsy appears to be statistically insignificant (FIG. 4A). Similarly, a combination of THC and H4-CBD significantly decreased core body temperature [F(1 ,28)=13.31 , p < 0.05] compared to A9-THC alone; however, no measurable significance was noted for H4-CBD alone on rectal temperature (FIG. 4B).

[0120] Novel Object Recognition. The object recognition test (ORT) is a commonly used behavioral assay to investigate various aspects of learning and memory in mice. For this assay, the mice had the initial object familiarization for 15 minutes post-THC administration. The data in the graph was obtained after the subsequent 4-hour consolidation period. A three-way interaction (p=0.01) was observed after removing one potential outlier. Overall, all groups showed a significant increase in test performance compared to control training, except the THC / vehicle (green bar) group, as anticipated with the THC-alone group (FIG. 5). The results showed that the combination of H4-CBD and A9-THC significantly improved mice's learning capacity and mitigated the cognitive impairment induced by A9-THC.Behavioral Tests and Novel Object Recognition Test for CBDP

[0121] Open Field (Total Horizontal Beam Breaks). The open field test showed a main effect of A9-THC to attenuate ambulations [F(1,42)=62.40, p < 0.05], In addition, a combination of CBDP and A9-THC also exerted a main effect of treatment to attenuate ambulations [F(1 ,42)=62.40, p < 0.05], CBDP alone tended to reduce ambulations but was not significant (p = 0.069) (FIG. 6).

[0122] Hot Plate and Tail Flick Observations. The hot plate test showed the primary effect of A9- THC to increase the latency to paw withdrawal [F(1,42)=48.91, p < 0.05] and exert antinociception. In addition, a combination of CBDP and A9-THC also exerted a main effect of treatment. We did not observe any effect of CBDP alone in increasing the latency to pawwithdrawal (FIG. 7A). Similarly, A9-THC significantly increased tail flick % MPE and a combination of CBDP and A9-THC (1:1) also exerted increased % MPE [F(2,40)=3.95, p < 0.05] (FIG. 7B).

[0123] Catalepsy and Core Body Temperature. The catalepsy test showed a main effect of A9- THC to increase the latency to paw withdrawal from an elevated bar indicating catalepsy [F(1,42)=12.78, p < 0.05], A combination of CBDP and A9-THC (1 :1) also exerted the catalepsy effect as observed for THC. No significant effects of CBDP alone were observed (FIG. 8A). In a similar fashion, A9-THC lowers the core body temperature [F(1 ,42)=62.62, p < 0.05], A similar trend was observed when a combination of CBDP and A9-THC (1 :1) was given to the mice. CBDP alone did not affect core body temperature (FIG. 8B).

[0124] Novel Object Recognition. We observed a significant interaction between the testing phase, A9-THC, and test compound (CBDP) condition [F(2,58)=3.19, p<0.05] (FIG. 9). All groups demonstrated significant learning from the training phase except for the THC-alone group. Since A9-THC induces cognitive and memory impairment, therefore it was anticipated that the A9-THC alone group would not improve the learning from the training phase. The results showed that the combination of CBDP and A9-THC significantly improved mice's learning capacity and mitigated the cognitive impairment induced by A9-THC.Conclusions

[0125] The present study identified two structurally-related natural and synthetic cannabidiol (CBD) compounds, CBDP and H4-CBD, as NAMs. in vitro experiments confirmed that H4-CBD and CBDP lack significant agonist activity, that CBDP inhibits the effects of CP55.940 activation of CB1 , and that CBDP - like CBD - does not compete for binding with orthosteric ligands of CB1 . The CB1 NAM effects were further explored in mitigating the A9-THC-induced impairment of cognitive function without altering the beneficial effects of THC considering tetrad effects (antinociception, hypothermia, hypolocomotion, and catalepsy) and novel object recognition test in combination with THC. A combination of either H4-CBD / CBDP with THC (1 :1 , 10+10 mg / kg) significantly improved mice's learning capacity and mitigated the cognitive impairment induced by A9-THC without altering the beneficial effects of A9-THC (antinociception). These CBD analogs, combined with A9-THC, could also treat obesity, drug abuse, and central nervous system (CNS) disorders.

[0126] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included within the scope of this disclosure and protected by the following claims.REFERENCES1. Castellano, C.; et al, Cannabinoids and memory: animal studies. Curr Drug Targets CNS Neurol Disord 2003, 2 (6), 389-402.2. Citti, C.; et al, A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Delta(9)-tetrahydrocannabinol: Delta(9)- Tetrahydrocannabiphorol. Sci Rep 2019, 9 (1), 20335.3. Ehrenreich, H.;et al, Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacology (Berl) 1999, 142 (3), 295-301.4. Elsohly, M. A.; et al, Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 2005, 78 (5), 539-48.5. Gamage, TF.; et al. In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol 2014, 25(2), 182-5.6. Horswill, JG. ; et al, PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats. Br J Pharmacol 2007, 152(5), 805-14.7. Jing, L.; et al. Effects of the cannabinoid CB(1) receptor allosteric modulator ORG 27569 on reinstatement of cocaine- and methamphetamine-seeking behavior in rats. Drug Alcohol Depend 2014, 143, 251-6.8. Kamal, B. S.; et al, Cannabis and the Anxiety of Fragmentation-A Systems Approach for Finding an Anxiolytic Cannabis Chemotype. Front Neurosci 2018, 12, 730-730.9. Pandey, P.; et al, Determination of the Negative Allosteric Binding Site of Cannabidiol at the CB1 Receptor: A Combined Computational and Site-Directed Mutagenesis Study. ACS Chem Neurosci 2025, doi: 10.1021 / acschemneuro.4c00343.10. Price, M.R.; et al, Allosteric modulation of the cannabinoid CB1 receptor, Mol Pharmacol 2005, 68(5), 1484-95.11. Radwan, M. M.; et al, Isolation and Pharmacological Evaluation of Minor Cannabinoids from High-Potency Cannabis sativa. J Nat Prod 2015, 78 (6), 1271-6.Ranganathan, M.; et al, The acute effects of cannabinoids on memory in humans:a review. Psychopharmacology (Berl) 2006, 188 (4), 425-44. Raux, PL.; et al. New perspectives on the role of the neurosteroid pregnenolone as an endogenous regulator of type-1 cannabinoid receptor (CB1 R) activity and function, J Neuroendocrinol 2021, e13034. Riedel, G.; et al, Cannabinoid function in learning, memory and plasticity. Handb Exp Pharmacol 2005, (168), 445-77. Shore, DM.; et al. Allosteric modulation of a cannabinoid G protein-coupled receptor: binding site elucidation and relationship to G protein signaling. J Biol Chem 2014, 289(9), 5828-45 Tham, M.; et al, Allosteric and orthosteric pharmacology of cannabidiol and cannabidioldimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol 2019, 176 (10), 1455-1469. Zagzoog, A. et al. (2020). In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa. Scientific reports, 10(1), 20405.

Claims

CLAIMSWhat is claimed is:

1. A pharmaceutical composition comprising a negative allosteric modulator (NAM) of cannabinoid receptor 1 (CB1), wherein the NAM comprises a compound of Formula I or a pharmaceutically acceptable ester, amide, salt, or prodrug thereof:Formula I wherein X is selected from H, OH, or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; wherein a bond between carbon atoms indicated by 1 and 2 is dihydro or dehydro; wherein two of R1a, ib, and Ricare OH, and wherein the ia, Rib, or Ricthat is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or / V-alkyl amide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof. wherein a carbon atom indicated by *** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; provided that the NAM is not CBD or abn-CBD; and provided that when R1aand R are OH, Ribis not linear alkyl.

2. The pharmaceutical composition of claim 1 , wherein Ricand Ribare OH and Riais selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

3. The pharmaceutical composition of claim 1 , wherein Riaand Ricare OH and R is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

4. The pharmaceutical composition of claim 1, wherein the Ria, R , or Ricthat is not OH is selected from:wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.

5. The composition of pharmaceutical composition of claim 1 , wherein the NAM is selected from:combination thereof.

6. The pharmaceutical composition of claim 1 , wherein the NAM comprises H4-CBD, CBDP, or any combination thereof.

7. The pharmaceutical composition of claim 1 , further comprising A9-tetrahydrocannabinol (THC).

8. The pharmaceutical composition of claim 7, wherein the composition comprises the NAM and the THC in a weight ratio of from about 1 :0.13 to about 1:1.

9. The pharmaceutical composition of claim 1, further comprising at least one carrier, diluent, or excipient.

10. The pharmaceutical composition of claim 9, wherein the at least one carrier, diluent, or excipient comprises a solvent, an emulsifier, a surfactant, or any combination thereof.

11. A method for treating or preventing a disease or disorder in a subject, the method comprising administering the pharmaceutical composition of any one of claims 1-10 to the subject.

12. The method of claim 11 , wherein the pharmaceutical composition is administered orally or parenterally.

13. The method of claim 11 , wherein the NAM is administered in an amount of from about 10 mg / kg of subject body weight to about 20 mg / kg of subject body weight.

14. The method of claim 11 , wherein the THC is administered in an amount of from about 10 mg / kg of subject body weight to about 20 mg / kg of subject body weight.

15. The method of claim 11 , wherein the disease or disorder comprises obesity, substance abuse, pain, anxiety, cancer, a neurodegenerative disorder, or another central nervous system (CNS) disorder.

16. The method of claim 15, wherein the cancer comprises acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, astrocytoma, basal cell carcinoma, bladder cancer, breast cancer, Burkitt’s lymphoma, carcinoid tumor, cervical cancer, chondroblastoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, cutaneous t-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer, extrahepatic bile duct cancer, gallbladder cancer, glioblastoma, glioma, hairy cell leukemia, head and neck cancer, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell carcinoma, Kaposi’s sarcoma, laryngeal cancer, lip and oral cavity cancer, liver cancer, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach cancer, testicular cancer, thymoma, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom’s macroglobulinemia, Wilms’ tumor, or any combination thereof.

17. The method of claim 15, wherein the neurodegenerative disorder comprises Alzheimer’s disease, amyotrophic lateral sclerosis, Friedrich ataxia, Huntington’s disease, Lewy body disease, Parkinson’s disease, spinal muscular atrophy, or any combination thereof.

18. The method of claim 15, wherein the CNS disorder comprises encephalitis, meningitis, stroke, multiple sclerosis, arachnoid cysts, attention-deficit / hyperactivity disorder, autism, catalepsy, epilepsy, infection, migraine, myelopathy, Tourette’s, or any combination thereof.

19. The method of claim 11 , wherein the NAM reduces or eliminates one or more THC side effects.

20. The method of claim 19, wherein the one or more side effects comprises altered senses, mood changes, impaired body movement, cognitive impairment, or any combination thereof.

21. The method of claim 11 , wherein the subject is a mammal.

22. The method of claim 21 , wherein the mammal is a human, cat, dog, goat, sheep, cattle, horse, swine, hamster, guinea pig, rat, rabbit, or mouse.

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