Beta-adrenergic receptor antagonists from kava

Abstract

Disclosed herein are novel kavalactone analogs. Also disclosed are methods of treating psychiatric disorders or other β-AR related disorders that involve administering a kavalactone analog disclosed, or a composition containing the same.

Description

Beta-Adrenergic Receptor Antagonists from KavaBACKGROUND

[0001] Kava (Piper methysticum), has been consumed as a traditional root powder- derived drink for centuries by the South Pacific Islanders. Its use globally, however, has increased in recent years. Kava is known for its ability to induce a sense of relaxation and improve sleep quality, but the mechanisms by which these effects occur remain to be fully elucidated.BRIEF DESCRIPTION OF DRAWINGS

[0002] Certain embodiments are illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings.

[0003] Figure 1 . (A) Yangonin (Y) and dihydromethysticin (DHM) exhibit noncompetitive inhibition against NE-induced cAMP in H1299 cells. This is indicated by the minimal shift in ECso and decrease of the max of the curve; whereas with propranolol (Prop), an orthosteric-binding beta-blocker, there is a shift in the EC50. (B) Prop significantly shifts the EC50 of NE, indicative of competitive inhibition. (C) Y and (D) DHM exhibit noncompetitive inhibition against NE-induced in a dose-dependent manner. The data is represented as normalized values between the top and bottom of the NE dose response curve obtained by nonlinear fit in GraphPad Prism8.

[0004] Figure 2. Y and DHM exhibit a slow mode of action compared to propranolol. The data are normalized to NC as 0% and NE as 100%.

[0005] Figure 3. The kavalactones exhibit noncompetitive inhibition against NE-induced cAMP with varying potencies. The data is represented as normalized values between the top and bottom of the NE dose response curve obtained by nonlinear fit in GraphPad Pris

[0006] Figure 4. (A) The kavalactone analogs exhibit noncompetitive inhibition against NE-induced cAMP with varying potencies. (B) Comparison of unoxidized (solid line) versus oxidized (dotted line) analogs. (C) Comparison of normal linker length (solid line) versus short linker (dotted line) analogs. (D) Comparison of kavalactone analogs with different aromatic substituents. m8.DETAILED DESCRIPTION

[0007] To explore the potential anxiolytic properties of kava, provided herein is data related to the effects of a specific class of kava-derived bioactive components called kavalactones on norepinephrine (NE)-induced adrenergic signaling in non-small cell lung cancer (NSCLC) H1299 cells. Since norepinephrine is an acute stress hormone, it was used as the stimulant in the studies described herein. Through these studies, it was found that a mixture of the six major kavalactones was able to inhibit NE-induced cyclic AMP (cAMP) production. This was determined by quantifying extracellular cAMP in H1299 cell medium after treatment via mixed-mode cation exchange solid phase extraction and ultraperformance liquid chromatography tandem mass spectrometry. Through the same analysis technique, it was found that out of the major kavalactones, yangonin was the most potent inhibitor of NE-induced cAMP in H1299.

[0008] In addition, by using known agonists of the adrenergic receptor (AR) subtypes, it was discovered that yangonin inhibits isoproterenol-induced cAMP production, indicating that yangonin inhibits (3-ARs. It was also discovered that yangonin is selective for (32-ARs over (31 -ARs in H1299 by using the agonists dobutamine and terbutaline, which bind to [31 - and [32-ARs, respectively. It is believed that this is the first demonstration of such unexpected finding. Known agonists and antagonists for (3-ARs all contain an amino group, with most containing a (3-hydroxy-amine motif, but kavalactones do not contain such a group. This led to the hypothesis that the kavalactones are allosteric modulators of (3-ARs; after forming dose response curves with NE in H1299 cells with and without kavalactone pre-treatment, it was found that thekavalactones were able to decrease the max of the curve of NE alone. This indicates that the kavalactones are potentially noncompetitive allosteric inhibitors of [3-ARs.

[0009] Further, it was discovered that kavalactones have a relatively slow mode of action; this was determined when studying the various treatment times of yangonin and dihydromethysticin against NE-induced cAMP. Altogether, the data provided herein supports that yangonin and other kavalactones are a non-amine-based negative allosteric modulator of p2-ARs with a slow mode of action.

[0010] To understand structure-activity relationships, the following kavalactone analogs were synthesized: The structures in Table 1 and 1 ) 5,6-dihydro-4-methoxy-6-(4- methoxyphenyl)-2H-pyran-2-one; 2) 6-benzo[1 ,3]dioxol-5-yl-4-methoxy-5,6-dihydro- pyran-2-one; 3) 4-methoxy-6-phenyl-5,6-dihydro-2H-pyran-2-one; 4) 5,6-dihydro-4- methoxy-6-(p-methoxyphenethyl)-2H-pyran-2-one; 5) 5,6-dihydroyangonin; 6) (E)-6-(2- (benzo[d][1 ,3]dioxol-5-yl)vinyl)-4-methoxy-2H-pyran-2-one; 7) 11 -methoxy yangonin; 8) (E)-4-methoxy-6-(3,4,5-trimethoxystyryl)-2H-pyran-2-one; 9) (E)-6-(2-(2,3- dihydrobenzo[b][1 ,4]dioxin-6-yl)vinyl)-4-methoxy-2H-pyran-2-one; 10) (E)-6-(4- (benzyloxy)styryl)-4-methoxy-2H-pyran-2-one; 11 ) (E)-6-(2-(1 H-indol-5-yl)vinyl)-4- methoxy-2H-pyran-2-one. These new analogs provide for translational potential of kava for psychiatric illnesses in which increased adrenergic signaling activation is involved including generalized anxiety disorder, bipolar disorder, and depression.

[0011] According to certain embodiments, disclosed are compounds or excipient containing-compositions comprising one or more of the kavalactone analogs described herein, as well as uses of the following compounds to treat a psychiatric disorder such as, but not limited to, anxiety, bipolar disorder, depression, and / or insomnia.as well enhancing libido.The enumerated compounds described herein may be synthesized in accord with the following general scheme:Table 2 below provides core structures of the compounds set forth above in Table 1 , which may include further substituents at various locations as described below in Table 3:Provided below in Table 3 are core kavalactone structures with defined substituents at various locations on the core structure:R1 = hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl; thioalkyl; alkylthio; sulfonyl; C1-C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C1-C6alkyl chain; or substituted branched Ci-Ce alkyl chain;R2=any substituent shown on the aromatic ring in Table 1R3= hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl;thioalkyl; alkylthio; sulfonyl; C1 -C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C1-C6 alkyl chain; or substituted branched C1- C6alkyl chain;R4= hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl; thioalkyl; alkylthio; sulfonyl; C1 -C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C1-C6 alkyl chain; or substituted branched C1- C6alkyl chain;R5= hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl; thioalkyl; alkylthio; sulfonyl; C1 -C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C-i-Ce alkyl chain; or substituted branched C1- C6alkyl chain;R6= hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl; thioalkyl; alkylthio; sulfonyl; C1 -C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C1-C6alkyl chain; or substituted branched C1- C6alkyl chain;R7= hydrogen; hydroxy, halo, haloalkyl, thiocarbonyl, alkoxy, alkenoxy, alkylaryloxy, aryloxy, arylalkyloxy, cyano; nitro; imino; alkylamino; aminoalkyl; thio; sulfhydryl; thioalkyl; alkylthio; sulfonyl; C1 -C6 straight or branched chain alkyl; C2-C6straight or branched chain alkenyl or alkynyl; aryl; aralkyl; heteroaryl; carbocycle or heterocycle group or moiety, or substituted straight C1-C6alkyl chain; or substituted branched C1- C6alkyl chain;Definitions

[0012] In the foregoing specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although various methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. However, the skilled artisan understands that the methods and materials used and described are examples and may not be the only ones suitable for use in the invention. Moreover, as measurements are subject to inherent variability, any temperature, weight, volume, time interval, pH, salinity, molarity or molality, range, concentration and any other measurements, quantities or numerical expressions given herein are intended to be approximate and not exact or critical figures unless expressly stated to the contrary. Any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements at the time of this writing.Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in specific nonlimiting examples are reported as precisely as possible.

[0013] Throughout this specification and the claims, unless the context requires otherwise, the word “comprise” and its variations, such as “comprises” and “comprising,” will be understood to imply the inclusion of a stated item, element or step or group of items, elements or steps but not the exclusion of any other item, element or step or group of items, elements or steps. Furthermore, the indefinite article “a” or “an” is meant to indicate one or more of the item, element or step modified by the article.

[0014] As used herein, the term “about” means plus or minus 20 percent of the recited value, so that, for example, “about 0.125” means 0.125 ±0.025, and “about 1.0” means1 .0 ±0.2. Furthermore, unless otherwise clear from the context, a numerical value presented herein has an implied precision given by the least significant digit. All ranges disclosed herein are to be understood to encompass any and all sub-ranges subsumed therein. For example, a range of "less than 10" can include any and all sub-ranges between (and including) the minimum value of zero and the maximum value of 10, that is, any and all sub-ranges having a minimum value of equal to or greater than zero and a maximum value of equal to or less than 10, e.g., 1 to 4.

[0015] The terms “treatment” and “therapy”, as used in the present application, refer to a set of hygienic, pharmacological, surgical and / or physical means used with the intent to cure and / or alleviate a disease and / or symptoms with the goal of remediating the health problem. The terms “treatment” and “therapy” include preventive and curative methods, since both are directed to the maintenance and / or re-establishment of the health of an individual or animal. Regardless of the origin of the symptoms, disease and disability, the administration of a suitable medicament to alleviate and / or cure a health problem should be interpreted as a form of treatment or therapy within the context of this application. Treating includes, but is not limited to, administering a composition comprising one or more active agents to a subject using any known method for purposes such as curing, reversing, alleviating, reducing the severity of, inhibiting the progression of, or reducing the likelihood of a disease, disorder, or condition or one or more symptoms or manifestations of a disease, disorder or condition.

[0016] The term “psychiatric disorder” refers to a diagnosis by a mental health professional of a behavioral or mental pattern that may cause suffering or a poor ability to function in life. “Psychiatric disorders” may be persistent, relapsing and remitting, or occur as a single episode. In a preferred embodiment, the term “psychiatric disorder” refers to one or more disorders selected from the following: alcohol and substance use disorders, anxiety disorders, panic disorder, agoraphobia and other specific phobias, social anxiety disorder, post-traumatic stress disorder, obsessive compulsive disorder, generalized anxiety disorder, bipolar disorder, sleep and wake disorders, depression, anorexia nervosa, binge eating disorder, bulimia nervosa, psychosis, schizophrenia,autism spectrum disorders, low libido, developmental disorders, and personality disorders.

[0017] The term “active agent,” as used herein, refers to the component of a pharmaceutical product or pharmaceutical composition which is biologically active. In the present application, an active agent may comprise one or more compounds. The term does not encompass inactive ingredients such as pharmaceutically active carriers and / or diluents.

[0018] The term “co-administer” or other grammatical forms thereof, as used herein refers to the administration of an active agent before, concurrently, or after the administration of another active agent such that the biological effects of either agents overlap.

[0019] The term “prevention”, as used in the present application, refers to a set of hygienic, pharmacological, surgical and / or physical means used to prevent the onset and / or development of a disease or disorder and / or symptoms thereof. The term “prevention” encompasses prophylactic methods, since these are used to maintain the health of an animal or individual.

[0020] The term Beta-adrenergic receptor (β-AR) related disorder refers to a disorder mediated by activation of a β-AR.

[0021] The terms “subject,” “individual,” and “patient,” are used interchangeably herein to refer to an animal being treated with one or more enumerated compounds as taught herein, including, but not limited to, simians, humans, avians, felines, canines, equines, rodents, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets. A suitable subject, also referred to herein as “subject in need” for methods described herein can be any animal, preferably a human, that is suspected of having, has been diagnosed as having, or is at risk of developing a disorder or disease that can be ameliorated, treated or prevented by administration of one or more enumerated compounds.

[0022] The terms “administering” or “administer” or “administration” as used herein with respect to an agent means providing the agent to a subject using any of the variousmethods or delivery systems for administering agents or pharmaceutical compositions known to those skilled in the art. Modes of administering include, but are not limited to oral administration, parenteral administration such as intravenous, subcutaneous, intramuscular or intraperitoneal injections, rectal administration by way of suppositories, transdermal administration, intraocular administration or administration by any route or method that delivers a therapeutically effective amount of the drug or composition to the cells or tissue to which it is targeted. Alternatively, routine experimentation will determine other acceptable routes of administration.

[0023] The term “adjunct anxiolytic agent” refers to an active agent that is known to have anxiolytic effects that are not an enumerated compound. Examples of adjunct anxiolytic agents include but are not limited to alprazolam, chlorodiazepoxide, clonazepam, clorzaepate, diazepam, halazeapam, lorazepam, oxazepam, imipramine, paroxetine, trazodone, venlafaxine, buspirone, hydroxyzine, or propanolol.

[0024] The term “enumerated compound(s)” as used herein encompass(es), for example, any kavalactone analog compound or activatable version thereof disclosed herein including any pharmaceutically acceptable salt or solvate thereof. Specific examples of compounds of the invention include those according to any chemical structure presented herein (Tables 1 -3) and any subgenera and / or species, or a pharmaceutically acceptable salt or solvate thereof. As used herein, the term “pharmaceutically acceptable salt” is intended to include nontoxic base addition salts. Suitable salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, and the like. The term “pharmaceutically acceptable salt” as used herein is also intended to include salts of acidic groups, such as a carboxylate, with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)-aminomethane), or with basessuch as piperidine or morpholine. Further examples of appropriate salts are described herein. Enumerated compound includes the disclosed structure or a stereoisomer thereof. The term “activatable version” refers to a form of a compound that includes a moiety that is removed upon administration wherein removal of the moiety converts the compound from an inactive version to active version. In specific examples, the enumerated compound is atheliapyrrolidine A (AP) or athelialpyrrolidine A-GIcA (APG).

[0025] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable diluent” means any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and, without limiting the scope of the present invention, include: additional buffering agents; preservatives; co-solvents; antioxidants, including ascorbic acid and methionine; chelating agents such as EDTA; metal complexes (e.g., Zn-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium, polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; organic sugars or sugar alcohols, such as lactitol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myoinisitose, myoinisitol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), polyethylene glycol; sulfur containing reducing agents, such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha]-monothioglycerol, and sodium thio sulfate; low molecular weight proteins, such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers, such as polyvinylpyrrolidone. Other pharmaceutically acceptable carriers, excipients, or stabilizers, such as those described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980) may also be included.

[0026] A “therapeutically effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration, or progression of the disorder being treated (e.g., psychiatricdisorder), prevent the advancement of the disorder being treated (e.g., psychiatric disorder), cause the regression of the disorder being treated (e.g., psychiatric disorder), or enhance or improve the prophylactic or therapeutic effects(s) of another therapy. The full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations per day for successive days.

[0027] B. Administration

[0028] An enumerated compound may be administered to an individual who suffers from a psychiatric and / or who is at risk of suffering from a psychiatric disorder. In a specific embodiment, the psychiatric disorder is anxiety.

[0029] In one embodiment, an enumerated compound in Table 1 may be administered to an individual who is suffering from a psychiatric disorder and / or who is at risk of suffering from a psychiatric disorder. Conversely, in an alternative embodiment, an enumerated compound may be administered as an adjunct therapeutic agent to an individual who is already being administered a compound to treat a psychiatric disorder, or who is at risk of a psychiatric disorder.

[0030] In a further embodiment, the enumerated compound is prepared for oral, sublingual, buccal, intranasal, intravenous, intramuscular, subcutaneous, rectal, transdermal, topical and / or inhalation-mediated administration routes, preferably oral, sublingual, inhalation-mediated and / or intranasal routes.

[0031] The pharmaceutical formulations of the present invention are prepared by methods well-known in the pharmaceutical arts. For example, the enumerated compounds are brought into association with a carrier and / or diluent, as a suspension or solution. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surface active agents, and the like) also are added. The choice of carrier is well within the prevue of the person of ordinary skill in the relevant art and is determined by the solubility and chemical nature of the compounds, chosen route of administration andstandard pharmaceutical practice. These accessory ingredients and materials are well known in the art and include (1 ) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11 ) buffering agents; (12) excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, and polyamide powder; (13) inert diluents, such as water or other solvents; (14) preservatives; (15) surface-active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl cellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monosterate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21 ) emulsifying and suspending agents; (22), solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan; (23) propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents which render the formulation isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials,such as lecithin; and (28) sweetening, flavoring, coloring, perfuming and preservative agents. Each such ingredient or material must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Ingredients and materials suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials for a chosen dosage form and method of administration may be determined using ordinary skill in the art. In a specific embodiment, the amount of an enumerated agent in a composition is i an amount between 0.1 mg and 400 mg.

[0032] For administration to a suitable subject, preferably to a human patient suffering from or suspected of suffering from a psychiatric related disorder and / or p-AR related disorder, the compounds described here are prepared according to methods known in the art into suitable formulations for any route of administration and suitable doses. Suitable subjects for administration and treatment can be any mammal, including rats, mice, dogs, cats, farm animals such as cattle, sheep, horses and the like or any mammal.3

[0033] C. Dosing and Dosage Forms

[0034] The appropriate dose of an enumerated compound depends upon a number of factors within the ken of the ordinarily skilled physician, veterinarian, or researcher for example, the identity, size, and condition of the subject or sample being treated, further depending upon the route by which the composition is to be administered, the frequency of administration, the severity of the disease, and the effect which the practitioner desires the an active agent to have. Furthermore, appropriate doses of an active agent depend upon the potency with respect to the expression or activity to be modulated. Such appropriate doses may be determined using the assays described herein or which are convenient to the practitioner and know in the art. When one or more of these active agents are to be administered to an animal (e.g., a human), a relatively low dose may be prescribed at first, with the dose subsequently increased until an appropriate response is obtained.

[0035] In addition, the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, gender, and diet of the subject, the time of administration, the route of administration, the rate of excretion, any drug combination, and the degree of expression or activity to be modulated.

[0036] Dosages and regimens for administration are determined by the person of skill, including physicians. Administration of compositions, including the compounds described here, can be performed a single time, or repeated at intervals, such as by continuous infusion or repeated oral doses, over a period of time, four times daily, twice daily, daily, every other day, weekly, monthly, or any interval to be determined by the skilled artisan based on the subject involved. Treatment can involve administration over a period of one day only, a week, a month, several months, years, or over a lifetime. Regimens and duration can vary according to any system known in the art, as is known to the skilled person.

[0037] Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste. These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or lyophilization processes.

[0038] Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like) may be prepared, e.g., by mixing the active ingredient(s) with one or more pharmaceutically acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, and / or coloring agents. Solid compositions of a similar type maybe employed as fillers in soft and hard- filled gelatin capsules using a suitable excipient. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine. The tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. The active ingredient can also be in microencapsulated form.

[0039] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms may contain suitable inert diluents commonly used in the art. Besides inert diluents, the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions may contain suspending agents.

[0040] Pharmaceutical compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable nonirritating carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Pharmaceutical compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such pharmaceutically acceptable carriers as are known in the art to be appropriate.

[0041] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops and inhalants. The active agent(s) / compound(s) may be mixed under sterile conditions with a suitable pharmaceutically acceptable carrier. The ointments, pastes, creams and gels may contain excipients. Powders and sprays may contain excipients and propellants.

[0042] Pharmaceutical compositions suitable for parenteral administrations comprise one or more agent(s) / compound(s) in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption.

[0043] In some cases, in order to prolong the effect of a drug (e.g., pharmaceutical formulation), it is desirable to slow its absorption from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.

[0044] The rate of absorption of the active agent / drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally- administered agent / drug may be accomplished by dissolving or suspending the active agent / drug in an oil vehicle. Injectable depot forms may be made by forming microencapsule matrices of the active ingredient in biodegradable polymers. Depending on the ratio of the active ingredient to polymer, and the nature of the particular polymer employed, the rate of active ingredient release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through a bacterial-retaining filter.

[0045] The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a lyophilized conditionrequiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.

[0046] When active agents are used in combinations, the dose of each agent is expected to be approximately the same as, or less than, an effective amount of either alone. For example, each pharmaceutically active ingredient can be administered in doses that are about 20% to about 80% of the dose in which each ingredient would be administered alone.

[0047] The two (or more) agents can be administered more or less simultaneously, i.e., concomitantly (e.g., within about 0 to about 5 minutes of each other, preferably within about a minute apart), or they can be administered at different times. For example, the compositions can be formulated in a unit dosage form, each dosage containing both active ingredients. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for human subjects and other animals, each unit containing a predetermined quantity of active material calculated to produce the desired prophylactic or therapeutic effect over the course of a treatment period, in association with the required pharmaceutical carrier.

[0048] D. Salts

[0049] Salts of the enumerated compounds disclosed herein include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2- ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, p- chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4'- methylenebis(3- hydroxy-2-ene-l -carboxylic acid), 3- phenylpropionic acid,trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. Salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine and the like.

[0050] This invention is not limited to the particular processes, compositions, or methodologies described, as these may vary. The terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the present invention, the preferred methods, devices, and materials are now described. All publications mentioned herein, are incorporated by reference in their entirety; nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.CLAIMSWhat is claimed is:1 . An enumerated compound.2. The enumerated compound of claim 1 selected from the following:

Claims

, or a pharmaceutically acceptable salt thereof.

3. A composition comprising at least one enumerated compound of claims 1 or 2 and a pharmaceutically acceptable carrier, wherein the at least one enumerated compound is, optionally, KA-83, KA-139 and / or KA-140.

4. The composition of claim 3, further comprising at least one adjunct anxiolytic agent.

5. The composition of claim 4, wherein the adjunct anxiolytic agent is selected from alprazolam, chlorodiazepoxide, clonazepam, clorzaepate, diazepam, halazeapam, lorazepam, oxazepam, imipramine, paroxetine, trazodone, venlafaxine, buspirone, hydroxyzine, or propranolol.

6. The composition of any of claims 3-5, wherein the enumerated compound is in an amount between 0.1 mg and 400 mg.

7. The composition of any of claims 3-6, wherein the adjunct anxiolytic agent is in an amount between 0.01 mg and 400 mg.

8. A method of treating and / or preventing a psychiatric disorder or |3-AR related disorder, in a subject in need thereof, the method comprising administering a therapeutically effective amount of an enumerated compound of claims 1 or 2, or a composition of any of claims 3-7.

9. The method of claim 8, wherein the psychiatric disorder comprises anxiety or insomnia.

10. The method of claim 8 or 9 wherein the method comprises co-administering at least one enumerated compound and at least one adjunct anxiolytic agent.1 1 .The method of claim 8 or 9, wherein the psychiatric disorder is low libido.

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