WO2009018368A1 - Combination treatment of nmda (n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor (daaoi) for neuropsychiatric disorders - Google Patents

Combination treatment of nmda (n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor (daaoi) for neuropsychiatric disorders Download PDF

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WO2009018368A1
WO2009018368A1 PCT/US2008/071632 US2008071632W WO2009018368A1 WO 2009018368 A1 WO2009018368 A1 WO 2009018368A1 US 2008071632 W US2008071632 W US 2008071632W WO 2009018368 A1 WO2009018368 A1 WO 2009018368A1
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phenyl
acid
methyl
propyl
chloro
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PCT/US2008/071632
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French (fr)
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Guochuan Emil Tsai
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Los Angeles Biomedical Research Institute At Harbor-Ucla Medical Center
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

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  • This is invention pertains the field of neuropsychiatry.
  • treatment methods are provided for neuropsychiatric disorders.
  • Schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder are examples of neuropsychiatric disorders.
  • Autism for example, is a developmental mental disorder characterized by autistic behavior, social failure, and language delay.
  • Alzheimer's Disease is a form of dementia that typically involves progressive mental deterioration, manifested by memory loss, confusion, and disorientation.
  • Alzheimer's Disease typically is treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil.
  • Attention Deficit Disorder is a disorder that is most prevalent in children and is associated with increased motor activity and a decreased attention span.
  • Attention Deficit Disorder commonly is treated by administration of psychostimulants such as Ritalin or Dexedrin. Depression is a clinical syndrome that includes a persistent sad mood or loss of interest in activities, which persists for at least two weeks in the absence of treatment. Conventional therapeutics include serotonin uptake inhibitors (e.g., PROZACTM), monoamine oxidase inhibitors, and tricyclic antidepressants.
  • PROZACTM serotonin uptake inhibitors
  • monoamine oxidase inhibitors e.g., monoamine oxidase inhibitors
  • tricyclic antidepressants e.g.
  • the term schizophrenia represents a group of neuropsychiatry disorders characterized by dysfunctions of the thinking process, such as delusions, hallucinations, and extensive withdrawal of the patient's interests from other people. Approximately one percent of the worldwide population is afflicted with schizophrenia, and this disorder is accompanied by high morbidity and mortality rates.
  • Conventional antipsychotic drugs which act on the dopamine D, receptor, can be used to treat the positive symptoms of schizophrenia, such as delusion and hallucination.
  • conventional antipsychotic drugs and the new atypical antipsychotic drugs, which act on the dopamine D, and 5HT2 serotonin receptor are limited in their ability to treat cognitive deficits and negative symptoms such as affect blunting (i.e., lack of facial expressions), anergia, and social withdrawal.
  • This invention pertains to the discovery that administration of any two or all three of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI) to a subject having or at high risk for a neuropsychiatric disorder, provides substantially greater efficacy at reducing or eliminating symptoms of the disorder than previously known single-agent therapeutic regimes.
  • this invention also provides pharmacological compositions comprising any two or all three agents in combination.
  • a pharmaceutical composition comprising a D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer and/or a glycine transporter inhibitor.
  • DAAOI D-amino Acid Oxidase Inhibitor
  • NMDA enhancer D-amino Acid Oxidase Inhibitor
  • a pharmaceutical composition is provided where the composition comprises a D-amino Acid Oxidase Inhibitor (DAAOI); and a glycine transporter inhibitor.
  • a pharmaceutical composition comprising a D-amino Acid Oxidase Inhibitor (DAAOI); an NMDA enhancer; and a glycine transporter inhibitor.
  • DAAOI D-amino Acid Oxidase Inhibitor
  • the D-amino Acid Oxidase Inhibitor comprises one or more agents is selected from the group consisting of 2-oxo-3-pentynoate;
  • Aminoguanidine (Guanylhydrazine; Carbamimidic hydrazide; Pimagedine; GER 11; Hydrazinecarboximidamide) or hydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt, nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, PABA, Vitamin Bx, Vitamin Hl); Methylglyoxal bis(guanylhydrazone) (also known as: Methyl GAG; Mitoguazone;
  • Phenothiazine (Thiodiphenylamine, 10H-Phenothiazine, AFI-Tiazin, Agrazine, Antiverm, Dibenzo-l,4-thiazine); 3,4-Dihydro-2H-l,4-thiazine-3,5-dicarboxylic acid (3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox [BANiINN], l-((5- Nitrofurfurylidene)amino)-2- methyltetrahydro-l,4-thiazine-4,4-dioxide, 3-Methyl-4-(51- nitrofurylidene-amino)- tetrahydro-4H-l,4-thiazine- 1,1 -dioxide, BAY 2502, 4-((5- Nitrofurfurylidene)amino)-3- methylthiomorpholine 1,1-dioxide
  • Diamino succinic acid CAS RN: 921-52-8 ); meso-2,3-Diaminosuccinic acid (CAS RN: 23220-52-2); Thiosemicarbazide (thiocarbamoyl hydrazide); Thiourea (Sulfourea; Thiocarbamide); Methylthiouracil (4(6)-Methyl-2-thiouracil, 4-Hydroxy-2-mercapto 6- methylpyrimidine); Sulphathiazole (Nl-(2-Thiazolypsulfanilamide, 4-Amino-N-2- thiazolylbenzenesulfonamide); Sulfathiazole Sodium Salt (4-Amino-N-2- thiazolylbenzenesulfonamide sodium salt); thiocyanate; 3-methylbenzyl thiocyanate; methimazole (2-mercapto-l-methylimidazole, l-methylimidazole-2-thiol);
  • the D-amino Acid Oxidase Inhibitor comprises one or more agents is selected from the group consisting benzoic acid; sodium benzoate; 2-aminobenzoate; 3- aminobenzoate; 4-aminobenzoate (p-aminobenzoate, aminoethylcysteine-ketimine, indole- 2-carboxylic acids, and benzo[d]isoxazol-3-ol derivatives.
  • the NMDA enhancer is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D- serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D- cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D- cycloserine, N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, , N,N-dimethylglycine, a salt of N,N-dimethylglycine, an ester of N,N-dimethylglycine, an alkylated N,N-dimethylgly
  • the composition is substantially free of D-cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine.
  • the glycine transporter inhibitor is selected from the group consisting of sarcosine (N-methyl glycine), N-[3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl]sarcosine, (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy- )propyl] sarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compunds, N- ⁇ 3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl ⁇ gl ycine ethyl ester, N- ⁇ 3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydro
  • the compositon further comprises an additional therapeutic agent, e.g., an antipsychotic, an antidepressant, a psychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic, and/or other psychotropics.
  • an additional therapeutic agent e.g., an antipsychotic, an antidepressant, a psychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic, and/or other psychotropics.
  • the additional therapeutic agent is one or more agents selected from the group consisting of Diazepam, Bromazepam, Prazepam, Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine de
  • Chlorprothixene Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, Ziprasidone, aripiprazole, Paliperidone, etc.
  • the composition is formulated as a unit dosage formulation.
  • the active agent(s) comprising the composition are independently formulated as salts, esters, or prodrugs.
  • the composition is formulated for administration by a route selected from the group consisting of oral administration, transdermal administration, intramuscular administration, rectal administration, intravenous administration, intrathecal administration, intraperitoneal administration, administration in a subcutaneous depot formulation, and administration as an inhalant.
  • DAAOI D-amino Acid Oxidase Inhibitor
  • DAAOI D-amino Acid Oxidase Inhibitor
  • NMDA enhancer an NMDA enhancer and/or a glycine transporter inhibitor
  • DAAOI a D-amino Acid Oxidase Inhibitor
  • DAAOI D-amino Acid Oxidase Inhibitor
  • DAAOI D-amino Acid Oxidase Inhibitor
  • DAAOI D-amino Acid Oxidase Inhibitor
  • the composition comprises any of the drug combinations described herein.
  • the neuropsychiatric disorder is schizophrenia. In certain embodiments the neuropsychiatric disorder is not schizophrenia. In certain embodiments the neuropsychiatric disorder is Alzheimer's disease. In certain embodiments the neuropsychiatric disorder is autism. In certain embodiments the neuropsychiatric disorder is depression. In certain embodiments the neuropsychiatric disorder is benign forgetfulness. In certain embodiments the neurpsychiatric disorder is a childhood learning disorder (e.g., attention deficit disorder). In certain embodiments the neuropsychiatric disorder is close head injury. In certain embodiments the neuropsychiatric disorder is anxiety disorders including obsessive compulsive disorder.
  • the neuropsychiatric disorder is close posttraumatic stress disorder. In certain embodiments the neuropsychiatric disorder is substance abuse. In certain typical embodiments the D-amino Acid Oxidase Inhibitor (DAAOI) is administered in a dosage ranging from 1 mg to about 150 g. . In certain typical embodiments the NMDA enhancer is administered at a dosage ranging from about 20 mg to about 150 g. In certain embodiments the glycine transporter inhibitor is administered at a dosage ranging from 10 mg to 50 g.
  • DAAOI D-amino Acid Oxidase Inhibitor
  • methods for mitigating one or more symptoms of a neuropsychiatric disorder ,where the methods involve comprising administering to a subject in need thereof a D-amino Acid Oxidase Inhibitor (DAAOI) at sufficient dosage to mitigate one or more symptoms of a neuropsychiatric disorder.
  • DAAOI D-amino Acid Oxidase Inhibitor
  • a pharmaceutical composition comprising an NMDA enhancer and/or a glycine transporter inhibitor.
  • a combination of an NMDA enhancer and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatry disorder and/or the use of a combination of D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder, and/orhe use of a combination of a D-amino Acid Oxidase Inhibitor (DAAOI); and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder, and/or the use of a combination of a D-amino Acid Oxidase Inhibitor (DAAOI), an NMDA enhancer; and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatry disorder and/or the use of
  • neuropsychiatric disorder refers to a disease having a pathophysiological component of attenuated NMDA receptor-mediated neurotransmission. Examples of such disorders include schizophrenia, Alzheimer's disease, dementia, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder.
  • schizophrenia refers to a psychiatric disorder that includes at least two of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms.
  • Alzheimer's Disease refers to a progressive mental deterioration manifested by memory loss, confusion and disorientation beginning in late middle life and typically resulting in death in five to ten years.
  • Pathologically, Alzheimer's Disease can be characterized by thickening, conglutination, and distortion of the intracellular neurofibrils, neurofibrillary tangles and senile plaques composed of granular or filamentous argentophilic masses with an amyloid core. Methods for diagnosing Alzheimer's Disease are known in the art.
  • NINCDS-ADRDA Alzheimer's Disease and Related Disorders Association
  • ADAS- cog Alzheimer's Disease Assessment Scale-cognitive subscale
  • Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. Patients can be diagnosed as suffering from dementia by using the DSM-IV criteria.
  • the term "autism” refers to a state of mental introversion characterized by morbid self-absorption, social failure, language delay, and stereotyped behavior. Patients can be diagnosed as suffering from autism by using the DSM-IV criteria.
  • depression refers to a clinical syndrome that includes a persistent sad mood or loss of interest in activities, which lasts for at least two weeks in the absence of treatment.
  • the DSM-IV criteria can be used to diagnose patients as suffering from depression.
  • Benign forgetfulness refers to a mild tendency to be unable to retrieve or recall information that was once registered, learned, and stored in memory (e.g., an inability to remember where one placed one's keys or parked one's car). Benign forgetfulness typically affects individuals after 40 years of age and can be recognized bystandard assessment instruments such as the Wechsler Memory Scale (Russell (1975) /. Consult Clin. Psychol. 43: 800-809).
  • childhood learning disorders refers to an impaired ability to learn, as experienced by certain children. Such learning disorders can be diagnosed by using the DSM-IV criteria.
  • the term "close head injury,” as used herein, refers to a clinical condition after head injury or trauma which condition can be characterized by cognitive and memory impairment. Such a condition can be diagnosed as "amnestic disorder due to a general medical condition” according to DSM-IV.
  • the term "attention deficit disorder,” as used herein, refers to at disorder that is most commonly exhibited by children and which can be characterized by increased motor activity and a decreased attention span. The DSM-IV criteria can be used to diagnose attention deficit disorder.
  • the terms "D-serine” and “D-alanine” refer to the D isomers of the amino acids serine and alanine, respectively. As D isomers, rather than L isomers, these amino acids are not naturally found in proteins.
  • Negative symptoms of schizophrenia include affect blunting, anergia, alogia and social withdrawal, which can be measured using SANS (the Scales for the Assessment of Negative Symptoms; see Andreasen (1983) Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).
  • “Positive” symptoms of schizophrenia include delusion and hallucination, which can be measured using PANSS (the Positive and Negative Syndrome Scale; see Kay et al. (1987) Schizophrenia Bulletin 13: 261-276).
  • "Cognitive” symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured by the Positive and Negative Syndrome Scale-cognitive subscale (PANS S -cognitive subscale) (Lindenmayer et al. (1994) /. Nerv. Ment. Dis.
  • A"full" agonist of the NMDA receptor is a compound that produces a maximal response at full receptor occupancy.
  • a "partial" agonist of the NMDA receptor is a compound that produces a lower maximal response at full receptor occupancy than do full agonists.
  • a "glycine uptake inhibitor of the NMDA receptor” is a compound that inhibits the re-uptake of glycine and increases the availability of glycine for the NMDA receptor (e.g., N-methylglycine).
  • the phrase "in conjunction with” when used in reference to the use of one or more drugs (active agents) described herein indicates that the drug(s) and the active agent(s) are administered so that there is at least some chronological overlap in their physiological activity on the organism.
  • the active agent(s) can be administered simultaneously and/or sequentially. In sequential administration there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second moiety as long as the first administered drug/agent has exerted some physiological alteration on the organism when the second administered agent is administered or becomes active in the organism.
  • Figure 1 The difference of startle responses between the initial and the last group of trials of single acoustic stimulus were considered the amount of habituation.
  • Amphetamatine (10 mg/kg) was administered 30 minutes before the experiments. There was no difference in the habituation at baseline across the groups (left).
  • Combination treatments induce a stronger habituation effect than benzoate or sarcosine treatment alone (middle).
  • the same trend of habituation (combination treatment >benzoate>sarcosine) was evident when amphetamine was administered and disrupted the habituation.
  • the combination treatment corrected the amphetamine-induced disruption of habituation back to normal state while single treatment of NMG or benzoate only partially correct the deficit (right).
  • Figure 2 Four groups of 10 mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of both sarcosine and benzoate (same doses as the individual treatment), or with vehicle for one week before the test. The mice continued to receive the drug until one week later when amphetamatine (10 mg/kg) was administered 30 minutes before the experiments. For PPI, stronger prepulse inhibited pulse response more (inhibition of 525 Hz>487Hz>468Hz). Amphetamine disrupted the inhibition in all treatments.
  • the invention provides methods for treating a patient diagnosed as suffering from a neuropsychiatric disorder or at high risk for a neuropsychiatric disorder, particularly a disorder characterized by a deficit in neurotransmission via the NMDA receptor (e.g., schizophrenia, Alzheimer's Disease, dementia, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder).
  • a neuropsychiatric disorder particularly a disorder characterized by a deficit in neurotransmission via the NMDA receptor (e.g., schizophrenia, Alzheimer's Disease, dementia, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder).
  • this invention pertains to the use of "combination" therapies, where the subjects are administered a combination of an NMDA (N-methyl-D- aspartate)-Enhancer, and/or a Glycine Transporter Inhibitor, and/or a D-amino Acid Oxidase Inhibitor (DAAOI).
  • NMDA N-methyl-D- aspartate
  • DAAOI D-amino Acid Oxidase Inhibitor
  • the administration of at two of these agents in conjunction with each other is contemplated, and in certain other embodiments, the administration of all three agents in conjunction with each other is contemplated.
  • the agents can be utilized individually as well.
  • DAAOI enhances the levels of both D-serine and D-alanine which are agonists of NMDA receptor and had been shown by the inventor to be beneficial for patients with schizophrenia. It can help a wide variety of patients with cognitive impairment and other mental or behavioral symptoms.
  • the combination therapies boost the NMDA activity and benefit subjects more than single agent treatments.
  • the novel treatment strategy can be applied to most if not all of them; for example, learning disorder, attention deficit and hyperactivity disorder, schizophrenia, depression, dementia.
  • the treatments described herein can be used in veterinary applications (e.g., to canines, felines, equines, bovines, porcines, etc.) with treatment of household pets (e.g., canine, feline) being of considerable interest.
  • the combination treatments described herein can improve cognition in animal models of learning and model of schizophrenia, depression, anxiety, and the like.
  • the treatment methods of the invention entail administering to a subject in need thereof (e.g., a patient diagnosed as having or at risk for a neuropsychiatric disorder) one or more a pharmaceutical compositions containing a therapeutically effective amount(s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI).
  • a subject in need thereof e.g., a patient diagnosed as having or at risk for a neuropsychiatric disorder
  • agents can be administered separately (simultaneously or sequentially), in a single "combination" formulation, or in simultaneously or sequentially a combination formulation comprising two agents and a second formulation comprising a single agent.
  • the effective doses of the active agent(s) can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective unit dose of typical compounds include: DAAOI (benzoate, range of 50 mg-150 grams), NMDA enhancers (D-serine, range of 50 mg-50 grams; D-alanine, range 1-150 grams), glycine transporter inhibitor (for example: sarcone, range 50 mg-50 grams); including DAAOI+NMDA enhancer, DAAOI+ glycine transporter inhibitor, NMDA enhancers +glycine transporter inhibitor or three classes of compound together.
  • DAAOI benzoate, range of 50 mg-150 grams
  • NMDA enhancers D-serine, range of 50 mg-50 grams
  • D-alanine range 1-150 grams
  • glycine transporter inhibitor for example: sarcone, range 50 mg-50 grams
  • DAAOI+NMDA enhancer DAAOI+ glycine transporter inhibitor
  • NMDA enhancers +glycine transporter inhibitor or three classes of compound together.
  • each of the active agent(s) ranges from 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg, 300 g, 20Og, 150 g, 100 g, 50 g, 25 g, 1Og, 5 g, or 1 g depending of factors including, but not limited to 150 g.
  • the compounds and compositions of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, it is estimated that a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary.
  • the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well-known to those skilled in the art.
  • the amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound(s) employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • appropriate dosages of the active agent(s) can readily be determined by those of ordinary skill in the art of medicine by monitoring the patient for signs of disease amelioration or inhibition, and increasing or decreasing the dosage and/or frequency of treatment as desired.
  • an amount equivalent to a dosage of 10 to 500 mg/day is administered to a patient in need of such treatment.
  • the dosage can be in an amount of 10, 50, 100, or 125 to 400 mg, such as 150 to 300 mg (e.g., 175 mg, 200 mg, 225 mg, or 250 mg).
  • the pharmaceutical compositions can be administered to the subject (e.g., patient) by any, or a combination, of several routes, such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular, or long term depot preparation.
  • routes such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular, or long term depot preparation.
  • solid compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.
  • suitable carriers or excipients such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release.
  • Disintegrators include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid.
  • Tablet binders that can be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch
  • liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents.
  • Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated.
  • injectable compositions can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).
  • the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused.
  • Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients.
  • a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water- for- Injection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil.
  • a pharmaceutical excipient such as Water- for- Injection, 0.9% saline, or 5% glucose solution
  • depot forms of the compounds e.g., decanoate, palmitate, undecylenic, enanthate
  • the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like.
  • compositions are contemplated.
  • such formulations contain at least two of the following three active agent(s): (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI).
  • all three active agent(s) are present in a single formulation.
  • the different components can be segregated, for example, in different layers of a tablet, in different microbeads/microcapsules, and the like.
  • two of more of the active agents are intermixed and/or suspended, e.g., in a single excipient.
  • the different active agent(s) will be provided each in a therapeutically effective dose.
  • D-amino Acid Oxidase Inhibitor (DAAOI) D-amino Acid Oxidase Inhibitor
  • D-amino Acid Oxidase Inhibitors suitable for use in the methods of the present invention are well known to those of skill in the art.
  • Suitable DAAOIs include, for example, but are not limited to 2-oxo-3-pentynoate; Aminoguanidine (Guanylhydrazine; Carbamimidic hydrazide; Pimagedine; GER 11;
  • Hydrazinecarboximidamide or hydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt, nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, PABA, Vitamin Bx, Vitamin Hl); Methylglyoxal bis(guanylhydrazone) (also known as: Methyl GAG; Mitoguazone;
  • Phenothiazine (Thiodiphenylamine, 10H- Phenothiazine, AFI-Tiazin, Agrazine, Antiverm, Dibenzo-l,4-thiazine); 3,4-Dihydro-2H-l,4- thiazine-3,5-dicarboxylic acid (3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox [BANrINN], l-((5-Nitrofurfurylidene)amino)-2- methyltetrahydro-l,4-thiazine-4,4-dioxide, 3-Methyl-4-(5 1 -nitrofurylidene-amino)- tetrahydro-4H-l,4-thiazine- 1,1 -dioxide, BAY 2502, 4- ((5-Nitrofurfurylidene)amino)-3- methylthiomorpho
  • preferred DAAOIs include, but are not limited to benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, aminoethylcysteine-ketimine, indole-2-carboxylic acids ⁇ see, e.g., PCT Publication WO 03/039540 which is incorporated herein by reference), and benzo[d]isoxazol-3-ol derivatives ⁇ see, e.g., U.S. Patent 7,166,725, which is incorporated herein by reference), and the like.
  • NMDA enhancers suitable for use in the methods of the present invention are well known to those of skill in the art.
  • Suitable NMDA enhancers include, for example, but are not limited to D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D- alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D-cycloserine, N-methylglycine, a salt of N- methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, , N 5 N- dimethylglycine, a salt of N,N-di
  • the composition is substantially free of D- cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine.
  • Glycine transporter inhibitors suitable for use in the methods of the present invention are well known to those of skill in the art.
  • Suitable glycine transporter inhibitors include, but are not limited to sarcosine (N-methyl glycine), N-[3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl]sarcosine, (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy- )propyl] sarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compunds ⁇ see, e.g., WO/2005/094514, which is incorporated herein by reference).
  • glycine transporter inhibitors include, but are not limited to N- ⁇ 3-[5-Cyano-l-(4- fluorophenyl)- l,3-dihydroisobenzofuran-l-yl]-l -propyl ⁇ gl ycine ethyl ester, N- ⁇ 3-[5- Cyano- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl ⁇ -N -methylglycine ethyl ester, N- ⁇ 3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl ⁇ gl ycine, N- ⁇ 3- [5-Cyano-l -(4-fluorophenyl)- l,3-dihydro
  • Patent 6,921,774 which is incorporated herein by reference), or other non glycine-, N-methylglycine- structurally based inhibitors (see, e.g., Harsing et al. (2006) Current Medicinal Chemistry, 13: 1017-1104)
  • the methods can involve administering additional therapeutic agents in conjunction with the agents described above.
  • the compositions can further comprise such additional therapeutic agents.
  • additional therapeutic agents include, but are not limited to antipsychotics, antidepressants, phsychostimulants, mood stablizers, anxiolytics, Alzheimer's disease therapeutics and other psychotropics.
  • additional therapeutic agents include, but are not limited to, Diazepam, Bromazepam, Prazepam, Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decan
  • Carotenoids Ginkgo Biloba, Statins, Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Selegiline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Velafaxine XR, Amphetamine, Methylphenidate,Metadate-CD, Modafinil, Adderall, Adderall XR, Dexedrine, Dexedrine Spansules, Desoxyn, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Rivastigmine,
  • compositions [0055] In certain embodiments, the agents described herein are administered separately, either simultaneously or sequentially.
  • the agents are commercially available in suitable pharmaceutically acceptable formulations.
  • the agents are provided as a combined formulations for administration by any of a variety of modalities including, but not limited to oral administration, rectal administration, injection, transdermal administration, subcutaneous depot administration, transdermal administration, and the like.
  • Methods of preparing combined formulations are well known to those of skill in the art (see, e.g., Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pennsylvania (1980), Remington: The Science and Practice of Pharmacy, 21st Ed. 2005, Lippincott Williams & Wilkins, and the like).
  • the active agent(s) inhibitor may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • wafer formulations for example, different layers comprising the wafer can contain different agents.
  • time-release capsules can comprise multiple active agents.
  • Such compositions and preparations are typically formulated to deliver the desired concentration of agent(s) over the desired time period.
  • kits treating (e.g., mitigating one or more symptoms of) a neuropsychiatric disorder.
  • the kits preferably comprise a container or containers containing the combinations of active agents described herein, either a separate formulations or as a single “combined" formulation.
  • the agent(s) can be provided in a unit dosage formulation (e.g. suppository, tablet, caplet, patch, etc.) and/or may be optionally combined with one or more pharmaceutically acceptable excipients.
  • kits optionally include labeling and/or instructional materials providing directions (i.e., protocols) for the practice of the methods or use of the
  • therapeutics or “prophylactics” of this invention.
  • Preferred instructional materials describe the use of combinations of agents as described herein to mitigate symptom(s) of a neuropsychiatric disorder and/or to prevent the onset or increase of one or more of such symptoms in an individual at risk for such a disorder.
  • the instructional materials can also, optionally, teach preferred dosages/therapeutic regiment, counter indications and the like.
  • instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
  • electronic storage media e.g., magnetic discs, tapes, cartridges, chips
  • optical media e.g., CD ROM
  • Such media may include addresses to internet sites that provide such instructional materials.
  • the startle reflex has served as a tool for studying fundamental properties of nervous function of complex behavioral states and cognitive processes.
  • the forebrain modulates several forms of startle plasticity including the habituation and PPI. Changes in startle magnitude through repeated stimulus presentations- habituation and sensitization-represent the simple forms of learning. Quantification of startle habituation and sensitization in rodent has direct physiological relevance to human CNS function. In fact, the most well accepted animal physiology models for schizophrenia are startle habituation and PPI.
  • startle magnitude is reduced when the pulse stimulus is preceded 30 to 500 msec by a weak prepulse.
  • This inhibition of a motor response elicited by a weak sensory event, termed PPI, provides an operational measure of sensorimotor gating.
  • Prepulse stimuli of 3, 6, or 12 dB above the 70 dB background noise inhibit the startle response elicited by 120-dB pulse stimuli.
  • Prestimuli used in intramodal studies of sensorimotor gating of acoustic startle are by the delivery of a discrete acoustic prepulse several msec before the startle pulse, with an intensity below startle threshold. Holding the interval between the prepulse and pulse stimuli constant at 100 msec typically yields suitable levels of PPI, ranging from 20% to 80% inhibition.
  • PPI 100 % x ⁇ [pulse-only units -(prepulse + pulse units)]/(pulse- onlyunits) ⁇ .
  • mice Male 129 SVE adult mice were first tested at baseline. Four groups of 10 mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of both sarcosine and benzoate (same doses as the individual treatment), or with vehicle for one week before the test. The mice continued to receive the drug until one week later when amphetamatine (10 mg/kg) was administered 30 minutes before the experiments.

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Abstract

The invention provides methods for treating neuropsychiatric disorders such as schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. The methods entail administering to a patient diagnosed as having a neuropsychiatric disorder or as at risk for a neuropsychiatric disorder administering to a D-amino Acid Oxidase Inhibitor (DAAOI); in conjunction with an NMDA enhancer and/or a glycine transporter inhibitor.

Description

COMBINATION TREATMENT OF NMDA (N-METHYL-D-
ASPARTATE)-ENHANCER, GLYCINE TRANSPORTER INHIBITOR,
D-AMINO ACID OXIDASE INHIBITOR (DAAOI) FOR
NEUROPSYCHIATRIC DISORDERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit of and priority to USSN 60/952,828, filed
July 30, 2007, which is incorporated herein by reference in its entirety for all purposes.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT r Not Applicable 1
FIELD OF THE INVENTION
[0002] This is invention pertains the field of neuropsychiatry. In particular treatment methods are provided for neuropsychiatric disorders.
BACKGROUND OF THE INVENTION [0003] Schizophrenia, Alzheimer's Disease, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder are examples of neuropsychiatric disorders. Autism, for example, is a developmental mental disorder characterized by autistic behavior, social failure, and language delay. Alzheimer's Disease is a form of dementia that typically involves progressive mental deterioration, manifested by memory loss, confusion, and disorientation. Alzheimer's Disease typically is treated by acetylcholine esterase inhibitors such as tacrine hydrochloride or donepezil. Attention Deficit Disorder is a disorder that is most prevalent in children and is associated with increased motor activity and a decreased attention span. Attention Deficit Disorder commonly is treated by administration of psychostimulants such as Ritalin or Dexedrin. Depression is a clinical syndrome that includes a persistent sad mood or loss of interest in activities, which persists for at least two weeks in the absence of treatment. Conventional therapeutics include serotonin uptake inhibitors (e.g., PROZACTM), monoamine oxidase inhibitors, and tricyclic antidepressants. [0004] The term schizophrenia represents a group of neuropsychiatry disorders characterized by dysfunctions of the thinking process, such as delusions, hallucinations, and extensive withdrawal of the patient's interests from other people. Approximately one percent of the worldwide population is afflicted with schizophrenia, and this disorder is accompanied by high morbidity and mortality rates.
[0005] Conventional antipsychotic drugs, which act on the dopamine D, receptor, can be used to treat the positive symptoms of schizophrenia, such as delusion and hallucination. In general, conventional antipsychotic drugs and the new atypical antipsychotic drugs, which act on the dopamine D, and 5HT2 serotonin receptor, are limited in their ability to treat cognitive deficits and negative symptoms such as affect blunting (i.e., lack of facial expressions), anergia, and social withdrawal.
SUMMARY OF THE INVENTION
[0006] This invention pertains to the discovery that administration of any two or all three of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI) to a subject having or at high risk for a neuropsychiatric disorder, provides substantially greater efficacy at reducing or eliminating symptoms of the disorder than previously known single-agent therapeutic regimes. In various embodiments, this invention also provides pharmacological compositions comprising any two or all three agents in combination. [0007] Accordingly, in certain embodiments, a pharmaceutical composition is provided where the composition comprises a D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer and/or a glycine transporter inhibitor. In certain embodiments, a pharmaceutical composition is provided where the composition comprises a D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer. In certain embodiments, a pharmaceutical composition is provided where the composition comprises a D-amino Acid Oxidase Inhibitor (DAAOI); and a glycine transporter inhibitor. In certain embodiments, a pharmaceutical composition is provided where the composition comprises a D-amino Acid Oxidase Inhibitor (DAAOI); an NMDA enhancer; and a glycine transporter inhibitor. In various embodiments of these compositions, the D-amino Acid Oxidase Inhibitor comprises one or more agents is selected from the group consisting of 2-oxo-3-pentynoate;
Aminoguanidine (Guanylhydrazine; Carbamimidic hydrazide; Pimagedine; GER 11; Hydrazinecarboximidamide) or hydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt, nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, PABA, Vitamin Bx, Vitamin Hl); Methylglyoxal bis(guanylhydrazone) ( also known as: Methyl GAG; Mitoguazone;
1,114(Methylethanediylidene)dinitrilo)diguanidine; Hydrazinecarboximidamide, 2,2'-(l- methyl-l,2-ethanediylidene)bis-; Pyruvaldehyde bis(amidinohydrazone); Megag; Mitoguazona [INN-Spanish] ; Guanidine, l,ll-((methylethanediylidene)dinitrilo)di-; 1,11- ((Methylethanediylidene)dinitrilo)diguanidine) ; Methylglyoxal bis(guanylhydrazone), dihydrochloride; phenylglyoxal bis(guanylhydrazone) (PhGBG); glyoxal bis(guanylhydrazone) (GBG; Guanidine, l,ll-(ethanediylidenedinitrilo)di(8Cl); Hydrazinecarboximidamide, 2,2'-(l,2-ethanediylidene)bis- (9Cl)); indole-propionic (IPA, 3-(3-Indolyl)propanoic acid); 3-indole-acetic acid (Heteroauxin, IAA); Indole-3-acetic acid Sodium salt; Indole-3-acetone; Indole- 3 -acetamide; Indole-3-acetyl-L-aspartic acid; Indole- 3-acetyl-L- alanine; Indole-3-acetylglycine; Indole-3-acetaldehyde Sodium Bisulfite
Addition compound; Indole- 3 -carboxylic acid; Indole-3-pyruvic acid (3-(3-Indolyl)-2- oxopropanoic acid); salicylic acid (2-Hydroxybenzoic acid); salicylic acid Sodium Salt; Salicylic acid Potassium Salt; Dansyl chloride (5-(Dimethylamino)naphthalene-l-sulfonyl chloride); Dansyl fluoride (5-(Dimethylamino)naphthalene-l-sulfonyl fluoride); dansyl glycine; Alanine tetrazole; benzoic tetrazole; tetrazole; Riboflavin 5 '-pyrophosphate (RPP, 5-Phospho-alpha-D-ribosyl diphosphate, PRib-PP, P-RPP); DL-propargylglycine (DL-PG, 2-Amino-4-pentynoic acid); L-C-Propargylglycine; N-Acetyl-DL-propargylglycine; (+)- Sodium 3-hydroxybutyrate; Trigonelline Hydrochloride (l-Methylpyridinium-3- carboxylate); N-methylnicotinate; Methyl 6-methylnicotinate; Ethyl 2-methylnicotinate; Kojic acid (2-Hydroxymethyl-5-hydroxy-gamma-pyrone, 5-Hydroxy-2- hydroxymethyl-4- pyranone); derivatives of kojic acid, such as: 6-(pyrrolidinomethyl)-kojic acid hydrochloride, 6-(morpholinomethyl)-kojic acid, 6- (diethylaminomethyl) -kojic acid hydrochloride; O-(2,4-dinitrophenyl)hydroxylamine; 2,4-dinitrophenyl glycine; Hydroxylamine Hydrochloride; Methyl-p-nitrobenzenesulfonate (Methyl A- nitrobenzenesulfonate); Aminoethylcysteine-ketimine (AECK, Thialysine ketimine, 2H- 1,4- Thiazine-5,6- dihydro-3-carboxylic acid, S-Aminoethyl-L-cysteine ketimine, 2H-1,4- Thiazine-3- carboxylic acid, 5,6-dihydro-); 1,4-thiazine derivatives; 4-Phenyl-l,4- sulfonazan (Tetrahydro-4-phenyl-4H-l,4-thiazine 1 -oxide, 4H- 1,4- Thiazine, tetrahydro-4- phenyl-, 1-oxide); 1. Phenothiazine (Thiodiphenylamine, 10H-Phenothiazine, AFI-Tiazin, Agrazine, Antiverm, Dibenzo-l,4-thiazine); 3,4-Dihydro-2H-l,4-thiazine-3,5-dicarboxylic acid (3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox [BANiINN], l-((5- Nitrofurfurylidene)amino)-2- methyltetrahydro-l,4-thiazine-4,4-dioxide, 3-Methyl-4-(51- nitrofurylidene-amino)- tetrahydro-4H-l,4-thiazine- 1,1 -dioxide, BAY 2502, 4-((5- Nitrofurfurylidene)amino)-3- methylthiomorpholine 1,1-dioxide); 3-(l-Pyrrolidinylmethyl)- 4-(5,6-dichloro-l-indancarbonyl)-tetrahydro-l,4-thiazine hydrochloride (R 84760; R 84761; Thiomorpholine, 4-((5,6-dichloro-2,3-dihydro-lHinden-l-yl)carbonyl)-3-(l- pyrrolidinylmethyl)-, monohydrochloride, (R-(R*,S*))-); ketimine reduced forms; cystathionine; cystathionine ketimine; lanthionine ketimine; thiomorpholine-2-carboxylic acid; thiomorpholine-2,6-dicarboxylic acid; TMDA (l,4-Thiomorpholine-3,5-dicarboxylic acid); 1-chloro-l-nitroethane; anthranilate; Ethyl 2-aminobenzoate (ethyl anthranilate); Methyl 2-aminobenzoate (Methyl anthranilate); picolinate; Ethyl picolinate (2- (Ethoxycarbonyl)pyridine, Ethyl 2-pyridinecarboxylate, L- Leucine methyl ester, hydrochloride; L-leucine ([(S)-(+)-leucine]); Fluorodinitrobenzene (l-Fluoro-2,4- dinitrobenzene, 2,4-DNFB, Benzene, l-fluoro2,4-dinitro-, VAN); Dinitrochlorobenzene (1- Chloro-2,4-dinitrobenzene, 1 ,3-Dinitro-4-chlorobenzene); 1 ,2-cyclohexanedione; Allylglycine (D-Allylglycine, 4-Pentenoic acid, 2-amino-); 2-amino-2,4-pentadienoate; 2- hydroxy-2,4-pentadienoate; 2-amino-4-keto-2-pentenoate; 2-hydroxybutyrate; Sodium 2- hydroxybutyrate; N-chloro-D-leucine; N-Acetyl-D-leucine; D-Leu (D-2-Amino-4- methylpentanoic acid); D-propargylglycine; 2-Amino-4-pentynoic acid; D,L- Propargylglycine; L-2-Amino4-pentynoic acid; Progesterone (4-Pregnene-3,20-dione); FAD (Flavin adenine dinucleotide , lH-Purin-6-amine, flavin dinucleotide, Adenosine 5'- (trihydrogen pyrophosphate), 5'-5'-ester with riboflavin); 6-OH-FAD; Phenylglyoxal (2,2- Dihydroxyacetophenone); Phenylglyoxal Monohydrate (2,2-Dihydroxyacetophenone monohydrate); Cyclothionine (Perhydro-l,4-thiazepine-3,5-dicarboxylic acid, 1,4- Hexahydrothiazepine-3,5-dicarboxylic acid, l,4-Thiazepine-3,5-dicarboxylic acid, hexahydro-); alpha-alpha'-iminodipropionic (Alanopine; 2,21-Iminodipropionic acid; L- Alanine, N-(l-carboxyethyl)-); Meso-Diaminosuccinic acid (3-Aminoaspartic acid ;
Diamino succinic acid; CAS RN: 921-52-8 ); meso-2,3-Diaminosuccinic acid (CAS RN: 23220-52-2); Thiosemicarbazide (thiocarbamoyl hydrazide); Thiourea (Sulfourea; Thiocarbamide); Methylthiouracil (4(6)-Methyl-2-thiouracil, 4-Hydroxy-2-mercapto 6- methylpyrimidine); Sulphathiazole (Nl-(2-Thiazolypsulfanilamide, 4-Amino-N-2- thiazolylbenzenesulfonamide); Sulfathiazole Sodium Salt (4-Amino-N-2- thiazolylbenzenesulfonamide sodium salt); thiocyanate; 3-methylbenzyl thiocyanate; methimazole (2-mercapto-l-methylimidazole, l-methylimidazole-2-thiol); dicarboxylic hydroxyacids; 1,3-Acetonedicarboxylic acid (3-Oxoglutaric acid); D-tartaric acid ([(25,35)- (-)-tartaric acid, unnatural tartaric acid]); L-tartaric acid ( [(2R,3R)-(+)-tartaric acid, natural tartaric acid]); DL-tartaric acid; potassium tartrate; D-malic acid; [(R)-(+)-malic acid, (R)- (+)-hydroxysuccinic acid]; L-malic acid; [(S)-(-)-malic acid, (S)-(-)-hydroxysuccinic acid]; DL-Malic acid (DL-hydroxysuccinic acid); Alpha-keto acids that are analogues of the amino acids alanine, leucine, phenylanaline, phenylglycine, tyrosine, serine, aspartate, and salts and derivatives thereof; pyruvic acid (2-Oxopropionic acid, alpha- Ketopropionic acid); sodium pyruvate; Pyruvic acid methyl ester (methyl pyruvate); Phenylpyruvic acid; Calcium phenylpyruvate (calcium pyruvate); Phenylpyruvic acid Sodium salt (Sodium phenylpyruvate); 4-hydroxyphenyl pyruvic acid; sodium alpha-ketoisovaleric acid (3- Methyl-2-oxobutyric acid Sodium salt, 3- Methyl-2-oxobutanoic acid sodium salt, a- Ketoisovaleric acid Sodium salt; Ketovaline Sodium salt); benzoylformic acid (a- Oxophenylacetic acid, Phenylglyoxylic acid); 4-methylthio-2-oxopentanoic acid; 4-Methyl- 2-oxopentanoic acid (4-Methyl-2-oxovaleric acid; alpha-Ketoisocaproic acid; ; A- methylthio-2-oxybutanoic acid; 2-oxybutanoic acid (hydroxybutyrate; 2-Hydroxybutyric acid; alpha-Hydroxy-nbutyric acid; DL-alpha-Hydroxybutyric acid Sodium Salt (sodium (+)-2-Hydroxybutyrate); Indole-3-pyruvic acid (alpha-Keto analogue of tryptophan ); The reaction product between cysteamine and bromopyruvate; cysteamine (2-Aminoethanethiol; 2-Mercaptoethylamine); pantetheine; 5-adenosylmethionine; Ethyl bromopyruvate; Methyl bromopyruvate; Bromopyruvate; and 5-S-Cysteinyldopamine. In various embodiments of these compositions, the D-amino Acid Oxidase Inhibitor comprises one or more agents is selected from the group consisting benzoic acid; sodium benzoate; 2-aminobenzoate; 3- aminobenzoate; 4-aminobenzoate (p-aminobenzoate, aminoethylcysteine-ketimine, indole- 2-carboxylic acids, and benzo[d]isoxazol-3-ol derivatives. In certain embodiments the NMDA enhancer is selected from the group consisting of D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D- serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D- cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D- cycloserine, N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, , N,N-dimethylglycine, a salt of N,N-dimethylglycine, an ester of N,N-dimethylglycine, an alkylated N,N-dimethylglycine, and N,N,N-trimethylglycine. In various embodiments the composition is substantially free of D-cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine. In certain embodiments the glycine transporter inhibitor is selected from the group consisting of sarcosine (N-methyl glycine), N-[3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl]sarcosine, (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy- )propyl] sarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compunds, N-{3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}gl ycine ethyl ester, N-{3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l- propyl}-N -methylglycine ethyl ester, N- { 3- [5-Cyano-l -(4-fluorophenyl)- 1,3- dihydroisobenzofuran-l-yl]-l -propyl }gl ycine, N-{3-[5-Cyano-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine, N- { 3- [ 1 -(3-chlorophenyl)- 1,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylg lycine, N- { 3- [ 1 -(3- trifluoromethylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [ 1 -(3-trifluoromethylphenyl)- 1 ,3 -dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methyl( 1 - ethyl)glycine, N- { 3-[ 1 -(4-methylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methylg lycine, N- { 3-[ 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methylg lycine, N- { 3-[ 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methyla lanine, N-{3-[l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}-N- methyl( l-ethyl)glycine, N-{3-[4-chloro-l-(3-methyl-4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [4-chloro- 1 -(4- chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5- chloro- 1 -(4-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylalanine, N- {3-[6-chloro-l-(3-methyl-4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N- methylglycine, N- { 3- [6-chloro- 1 -(4-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl } - N-methylglycine, N- { 3-[6-chloro- 1 -(4-methylphenyl)- 1 ,3-dihydroisobenzofuran- l-yl]-l -propyl}- N-methylglycine, N-{3-[6-chloro-l-(4-methoxyphenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3-[5-fhαoro- 1 -(4- chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5-fluoro- 1 -(4-methoxyphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [5-trifruoromethyl- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methylglycine, N- { 3- [5-trifruoromethyl- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl }-N-methylalanine, N-{3-[5-cyano-l-(3-methyl-4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 - propyl } -N-methylglycine, N- { 3- [5-cyano- 1 -(4- cyanophenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N- methylalanine, N-{3-[5-cyano- l-(4-methoxyphenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}- N-methylglycine, N-{3- [5-cyano- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine, N-{2-[5-cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]ethyl} -N-met hylglycine, N- { 3- [5-Chloro-l-(4-chloro-phenyl)-indan-l-yl] -propyl} -N-methylglycine, N- {3- [5- Chloro-l-(4-chloro-phenyl)-indan-l-yl] -propyl }-N-methylalanine, N-{3-[3-cyclo-l-(4- methylphenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N -methylglycine, N-[3-(3,3- Dimethyl- 1 -phenyl- 1 ,3-dihydro-benzo[c] thiophen- 1 -yl)-propyl] -N-me thylglycine, N- [3- (3,3-Dimethyl-l-phenyl-l,3-dihydro-benzo[c]thiophen-l-yl)-propyl]-N-me thylalanine, N- {3-[l-(4-Fluoro-phenyl)-3-dimethyl-l,3-dihydro-isobenzofuran-l-yl]-propyl }-N- methylglycine, N-{3-[5-Bromo-l-(4-chlorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l- propyl}-N -methylglycine, N-{2-[l-(4-Chloro-phenyl)-3,3-dimethyl-l,3-dihydro- isobenzofuran- 1 -yl] -ethy 1 } -N-methylglycine, N- [3-(3-methyl- 1 -phenyl- lH-inden- 1-yl)- propyl] -N-methylglycine, N-[3-(5-Chloro-l-thiophen-2-yl-l,3-dihydro-isobenzofuran-l-yl)- propyl]-N-me thylglycine, N-[3-(5-Chloro-l-thiophen-2-yl-l,3-dihydro-isobenzofuran-l- yl)-propyl]-N-me thyl(l-ethyl)-glycine, N- [3-(3-methyl-l -phenyl- 1,3-dihydro- isobenzofuran-l-yl)-propyl]-N-methylala nine, N- [3-(3-methyl-l -phenyl- 1,3-dihydro- isobenzofuran-l-yl)-propyl]-N-methyl(l- ethyl)-glycine, N-[3-(3,3-Dimethyl-l-phenyl-l,3- dihydro-isobenzofuran-l-yl)-ethyl]-N-methyl alanine, N-[3-(3,3-Dimethyl-l-(4-fluoro- phenyl)-l,3-dihydro-isobenzofuran-l-yl)-ethy l]-N-methylalanine, N-[3-(3,3-Dimethyl-l- phenyl-l,3-dihydro-isobenzofuran-l-yl)-ethyl]-N-methyl -(l-ethyl)glycine, N-[3-(3,3- Dimethyl- l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)-ethy l]-N-methyl-(l- ethyl)glycine, N-[3-(3,3-Diethyl-l -phenyl- l,3-dihydro-isobenzofuran-l-yl)-propyl]-N- methyl alanine, N-[3-(3,3-Diethyl-l-(4-chloro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)- propy l]-N-methylalanine, N-[3-(3,3-Diethyl-l-(4-chloro-phenyl)-l,3-dihydro- isobenzofuran-l-yl)-propy l]-N-methylglycine, N-[3-(l-phenyl-l,3-dihydro- benzo[c]thiophen-l-yl)-propyl]-N-methylalanine, N-{3-[l-(4-Chloro-phenyl)-3,3-dimethyl- indan-1-yl] -propyl }-N-methylglycine, N-{3-[l-(4-Chloro-phenyl)-3,3-diethyl-l,3-dihydro- isobenzofuran-1-yl] -propy l}-N-methyl-alanine, N-[2-(3-methyl-l-phenyl-indan-l-yl)- ethyl] -amino }-N-methyl alanine, N-[3-(l-phenyl-(lH)-inden-l-yl)-propyl]-N-methyl- alanine, N-{3-[l-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-l,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] - propyl } -N-methyl-glycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl } -N- methyl-alanine, N-{3-[l-(4-chloro-phenyl)-5-(4-trifluoromethyl-phenyl)-l,3-dihydro- isobenzo furan- 1-yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-methyl- phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro- phenyl)-5-(4-methoxy-phenyl)-l,3-dihydro-isobenzofuran-l- yl] -ethyl} -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5 -(2-thiophenyl)- 1 ,3-dihydro-isobenzofuran- 1-yl] - ethyl } -N- methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-methyl-phenyl)-l,3-dihydro- isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5 -(4-methoxy- phenyl)- 1 ,3-dihydro-isobenzofuran- 1 - yl] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-chloro- phenyl)-5-(4-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1-yl] -propyl } -N-methyl- glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5-(4-chloro-phenyl)- 1 ,3-dihydro-isobenzofuran- 1-y I]- ethyl} -N-methyl-glycine, N-{2-[l-(4-Chloro-phenyl)-5-(5-chloro-thiophen-2-yl)-l,3- dihydro-isobenzofu ran- 1-yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3- methyl-phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4- Chloro-phenyl)-5-(2-methyl-phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1- yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-chloro-phenyl)-5-(3-trifluoromethyl-phenyl)-l,3- dihydro-isobenzo furan- 1 -yl] -ethyl } -N-methyl-glycine, N- { 3- [ 1 -(4-chloro-phenyl)-5-(3 - trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-l,3-dihydro-isobenzofuran - 1-yl] -ethyl} -N- methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-l,3-dihydro- isobenzofuran-1-y 1] -propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3-methyl- phenyl)- 1 ,3-dihydro-isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro- phenyl)-5-(2-methyl -phenyl)- 1,3-dihydro-isobenzofuran- 1-y l] -propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1-yl]- propyl}-N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-l,3- dihydro-isobenzofuran -1-yl] -propyl }-N-methyl-glycine, and N-{3-[l-(4-chloro-phenyl)-5- (2-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1-yl] -propyl } -N-methyl-glycine. In various embodiments the compositon further comprises an additional therapeutic agent, e.g., an antipsychotic, an antidepressant, a psychostimulant, a mood stabilizer, an anxiolytic, an Alzheimer's disease therapeutic, and/or other psychotropics. In certain embodiments the additional therapeutic agent is one or more agents selected from the group consisting of Diazepam, Bromazepam, Prazepam, Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Risperdal Consta, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Citalopram, S-Citalopram, Clomipramine, , Desipramine, Doxepin, Duloxetine, Milnacipran, Fluoxetine, Fluvoxamine, Imipramine, Isocarboxazid, Lamatrogine, Lithium, Topiramate, Gabapentin, Carbamazepine, Oxacarbazepine, Valporate, Maprotiline, Memantine, Mirtazapine, Brofaromine, Gepirone, Moclobemide, Physostigmine,, Nicotine, Huperzine Alpha, vitamine C, vitamine E, Carotenoids, Ginkgo Biloba, Statins, Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Selegiline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Velafaxine XR, Amphetamine, Methylphenidate,Metadate-CD, Modafinil, Adderall, Adderall XR, Dexedrine, Dexedrine Spansules, Desoxyn, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Rivastigmine, Acetophenazine,
Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, Ziprasidone, aripiprazole, Paliperidone, etc.
[0008] In certain embodiments the composition is formulated as a unit dosage formulation. In certain embodiments the active agent(s) comprising the composition are independently formulated as salts, esters, or prodrugs. In certain embodiments the composition is formulated for administration by a route selected from the group consisting of oral administration, transdermal administration, intramuscular administration, rectal administration, intravenous administration, intrathecal administration, intraperitoneal administration, administration in a subcutaneous depot formulation, and administration as an inhalant.
[0009] Also provided are methods of mitigating one or more symptoms of a neuropsychiatric disorder. The methods typically involve administering to a subject in need thereof a D-amino Acid Oxidase Inhibitor (DAAOI); in conjunction with an NMDA enhancer and/or a glycine transporter inhibitor and/or administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with an NMDA enhancer, and/or administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with a glycine transporter inhibitor, and/or administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with an NMDA enhancer and a glycine transporter inhibitor, and/or administering a NMDA enhancer in conjunction with a glycine transporter inhibitor. In certain embodiments the composition comprises any of the drug combinations described herein. In certain embodiments the neuropsychiatric disorder is schizophrenia. In certain embodiments the neuropsychiatric disorder is not schizophrenia. In certain embodiments the neuropsychiatric disorder is Alzheimer's disease. In certain embodiments the neuropsychiatric disorder is autism. In certain embodiments the neuropsychiatric disorder is depression. In certain embodiments the neuropsychiatric disorder is benign forgetfulness. In certain embodiments the neurpsychiatric disorder is a childhood learning disorder (e.g., attention deficit disorder). In certain embodiments the neuropsychiatric disorder is close head injury. In certain embodiments the neuropsychiatric disorder is anxiety disorders including obsessive compulsive disorder. In certain embodiments the neuropsychiatric disorder is close posttraumatic stress disorder. In certain embodiments the neuropsychiatric disorder is substance abuse. In certain typical embodiments the D-amino Acid Oxidase Inhibitor (DAAOI) is administered in a dosage ranging from 1 mg to about 150 g. . In certain typical embodiments the NMDA enhancer is administered at a dosage ranging from about 20 mg to about 150 g. In certain embodiments the glycine transporter inhibitor is administered at a dosage ranging from 10 mg to 50 g.
[0010] In certain embodiments methods are provided for mitigating one or more symptoms of a neuropsychiatric disorder ,where the methods involve comprising administering to a subject in need thereof a D-amino Acid Oxidase Inhibitor (DAAOI) at sufficient dosage to mitigate one or more symptoms of a neuropsychiatric disorder. [0011] In certain embodiments a pharmaceutical composition is provided comprising an NMDA enhancer and/or a glycine transporter inhibitor.
[0012] Also provided is the use of a combination of an NMDA enhancer and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatry disorder and/or the use of a combination of D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder, and/orhe use of a combination of a D-amino Acid Oxidase Inhibitor (DAAOI); and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder, and/or the use of a combination of a D-amino Acid Oxidase Inhibitor (DAAOI), an NMDA enhancer; and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder.
DEFINITIONS [0013] As used herein, the term "neuropsychiatric disorder" refers to a disease having a pathophysiological component of attenuated NMDA receptor-mediated neurotransmission. Examples of such disorders include schizophrenia, Alzheimer's disease, dementia, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder. [0014] As used herein, the term "schizophrenia" refers to a psychiatric disorder that includes at least two of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, or negative symptoms. Patients can be diagnosed as schizophrenic using the DSMIV criteria (APA, 1994, Diagnostic and Statistical Manual of 30 Mental Disorders (Fourth Edition), Washington, D.C.). [0015] The term "Alzheimer's Disease" refers to a progressive mental deterioration manifested by memory loss, confusion and disorientation beginning in late middle life and typically resulting in death in five to ten years. Pathologically, Alzheimer's Disease can be characterized by thickening, conglutination, and distortion of the intracellular neurofibrils, neurofibrillary tangles and senile plaques composed of granular or filamentous argentophilic masses with an amyloid core. Methods for diagnosing Alzheimer's Disease are known in the art. For example, the National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease — and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria can be used to diagnose Alzheimer's Disease (McKhann et al. (1984) Neurology 34: 939-944). The patient's cognitive function can be assessed by the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS- cog; Rosen et al. (1984) Am. J. Psychiatry 141: 1356-1364).
[0016] Dementia is the progressive decline in cognitive function due to damage or disease in the brain beyond what might be expected from normal aging. Patients can be diagnosed as suffering from dementia by using the DSM-IV criteria. [0017] As used herein, the term "autism" refers to a state of mental introversion characterized by morbid self-absorption, social failure, language delay, and stereotyped behavior. Patients can be diagnosed as suffering from autism by using the DSM-IV criteria.
[0018] As used herein, the term "depression" refers to a clinical syndrome that includes a persistent sad mood or loss of interest in activities, which lasts for at least two weeks in the absence of treatment. The DSM-IV criteria can be used to diagnose patients as suffering from depression.
[0019] The term "benign forgetfulness," as used herein, refers to a mild tendency to be unable to retrieve or recall information that was once registered, learned, and stored in memory (e.g., an inability to remember where one placed one's keys or parked one's car). Benign forgetfulness typically affects individuals after 40 years of age and can be recognized bystandard assessment instruments such as the Wechsler Memory Scale (Russell (1975) /. Consult Clin. Psychol. 43: 800-809).
[0020] As used herein, the term "childhood learning disorders" refers to an impaired ability to learn, as experienced by certain children. Such learning disorders can be diagnosed by using the DSM-IV criteria.
[0021] The term "close head injury," as used herein, refers to a clinical condition after head injury or trauma which condition can be characterized by cognitive and memory impairment. Such a condition can be diagnosed as "amnestic disorder due to a general medical condition" according to DSM-IV. [0022] The term "attention deficit disorder," as used herein, refers to at disorder that is most commonly exhibited by children and which can be characterized by increased motor activity and a decreased attention span. The DSM-IV criteria can be used to diagnose attention deficit disorder. [0023] The terms "D-serine" and "D-alanine" refer to the D isomers of the amino acids serine and alanine, respectively. As D isomers, rather than L isomers, these amino acids are not naturally found in proteins.
[0024] "Negative" symptoms of schizophrenia include affect blunting, anergia, alogia and social withdrawal, which can be measured using SANS (the Scales for the Assessment of Negative Symptoms; see Andreasen (1983) Scales for the Assessment of Negative Symptoms (SANS), Iowa City, Iowa).
[0025] "Positive" symptoms of schizophrenia include delusion and hallucination, which can be measured using PANSS (the Positive and Negative Syndrome Scale; see Kay et al. (1987) Schizophrenia Bulletin 13: 261-276). [0026] "Cognitive" symptoms of schizophrenia include impairment in obtaining, organizing, and using intellectual knowledge which can be measured by the Positive and Negative Syndrome Scale-cognitive subscale (PANS S -cognitive subscale) (Lindenmayer et al. (1994) /. Nerv. Ment. Dis. 182: 631-638) or with cognitive tasks such as the Wisconsin Card Sorting Test and battery of Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS, "www.matrics.ucla.edu/matrics-psychometrics- frame.htm").
[0027] A"full" agonist of the NMDA receptor is a compound that produces a maximal response at full receptor occupancy.
[0028] A "partial" agonist of the NMDA receptor is a compound that produces a lower maximal response at full receptor occupancy than do full agonists.
[0029] A "glycine uptake inhibitor of the NMDA receptor" is a compound that inhibits the re-uptake of glycine and increases the availability of glycine for the NMDA receptor (e.g., N-methylglycine).
[0030] The phrase "in conjunction with" when used in reference to the use of one or more drugs (active agents) described herein indicates that the drug(s) and the active agent(s) are administered so that there is at least some chronological overlap in their physiological activity on the organism. Thus the active agent(s) can be administered simultaneously and/or sequentially. In sequential administration there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second moiety as long as the first administered drug/agent has exerted some physiological alteration on the organism when the second administered agent is administered or becomes active in the organism.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Figure 1. The difference of startle responses between the initial and the last group of trials of single acoustic stimulus were considered the amount of habituation. Three groups of mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of both sarcosine and benzoate. Amphetamatine (10 mg/kg) was administered 30 minutes before the experiments. There was no difference in the habituation at baseline across the groups (left). Combination treatments induce a stronger habituation effect than benzoate or sarcosine treatment alone (middle). The same trend of habituation (combination treatment >benzoate>sarcosine) was evident when amphetamine was administered and disrupted the habituation. The combination treatment corrected the amphetamine-induced disruption of habituation back to normal state while single treatment of NMG or benzoate only partially correct the deficit (right).
[0032] Figure 2. Four groups of 10 mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of both sarcosine and benzoate (same doses as the individual treatment), or with vehicle for one week before the test. The mice continued to receive the drug until one week later when amphetamatine (10 mg/kg) was administered 30 minutes before the experiments. For PPI, stronger prepulse inhibited pulse response more (inhibition of 525 Hz>487Hz>468Hz). Amphetamine disrupted the inhibition in all treatments. For example, in 487 Hz paradigm, the disruption by amphetamine is most pronounced in vehicle-treated mice (left column), partially corrected by either sarcosine (NMG) or benzoate (middle 2 columns) and was best corrected by the combination treatment (right column). DETAILED DESCRIPTION
[0033] The invention provides methods for treating a patient diagnosed as suffering from a neuropsychiatric disorder or at high risk for a neuropsychiatric disorder, particularly a disorder characterized by a deficit in neurotransmission via the NMDA receptor (e.g., schizophrenia, Alzheimer's Disease, dementia, autism, depression, benign forgetfulness, childhood learning disorders, close head injury, and attention deficit disorder). As described above, a variety of methods for diagnosing these disorders are known to those of skill in the art of clinical psychiatry, and any conventional diagnostic method can be used in conjunction with the invention., [0034] In various embodiments this invention pertains to the use of "combination" therapies,, where the subjects are administered a combination of an NMDA (N-methyl-D- aspartate)-Enhancer, and/or a Glycine Transporter Inhibitor, and/or a D-amino Acid Oxidase Inhibitor (DAAOI). In certain embodiments the administration of at two of these agents in conjunction with each other is contemplated, and in certain other embodiments, the administration of all three agents in conjunction with each other is contemplated. In various embodiments the agents can be utilized individually as well.
[0035] Previous treatments using NMDA enhancer or glycine transporter inhibitor alone have had limited efficacy. It was discovered that the use of a DAAOI alone or the combination treatment(s) described above, results in unexpected and surprising improvement in subjects so treated (e.g., with cognitive impairment and other mental or behavioral symptoms).
[0036] Without being bound to a particular theory, it is believed that DAAOI enhances the levels of both D-serine and D-alanine which are agonists of NMDA receptor and had been shown by the inventor to be beneficial for patients with schizophrenia. It can help a wide variety of patients with cognitive impairment and other mental or behavioral symptoms. The combination therapies boost the NMDA activity and benefit subjects more than single agent treatments.
[0037] Most of the neuropsychiatric disorders present with cognitive deficits, behavioral and mental symptoms. The novel treatment strategy can be applied to most if not all of them; for example, learning disorder, attention deficit and hyperactivity disorder, schizophrenia, depression, dementia. In addition to their benefits for human subjects, the treatments described herein can be used in veterinary applications (e.g., to canines, felines, equines, bovines, porcines, etc.) with treatment of household pets (e.g., canine, feline) being of considerable interest. In addiction, the combination treatments described herein can improve cognition in animal models of learning and model of schizophrenia, depression, anxiety, and the like. [0038] In certain embodiments the treatment methods of the invention entail administering to a subject in need thereof (e.g., a patient diagnosed as having or at risk for a neuropsychiatric disorder) one or more a pharmaceutical compositions containing a therapeutically effective amount(s) of (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI). Where combinations of two or all three of these agents are utilized they can be administered separately (simultaneously or sequentially), in a single "combination" formulation, or in simultaneously or sequentially a combination formulation comprising two agents and a second formulation comprising a single agent.
[0039] The effective doses of the active agent(s) (of an NMDA (N-methyl-D- aspartate)-Enhancer, and/or Glycine Transporter Inhibitor, and/or D-amino Acid Oxidase Inhibitor (DAAOI)) can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered. In various embodiments, for human patients, the effective unit dose of typical compounds include: DAAOI (benzoate, range of 50 mg-150 grams), NMDA enhancers (D-serine, range of 50 mg-50 grams; D-alanine, range 1-150 grams), glycine transporter inhibitor (for example: sarcone, range 50 mg-50 grams); including DAAOI+NMDA enhancer, DAAOI+ glycine transporter inhibitor, NMDA enhancers +glycine transporter inhibitor or three classes of compound together.
[0040] In various embodiments, then, effective doses of each of the active agent(s) ranges from 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, or 500 mg, 300 g, 20Og, 150 g, 100 g, 50 g, 25 g, 1Og, 5 g, or 1 g depending of factors including, but not limited to 150 g. In certain embodiments the compounds and compositions of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, it is estimated that a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well-known to those skilled in the art. The amount of active ingredient(s) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound(s) employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. [0041] In all of the methods of the invention, appropriate dosages of the active agent(s) can readily be determined by those of ordinary skill in the art of medicine by monitoring the patient for signs of disease amelioration or inhibition, and increasing or decreasing the dosage and/or frequency of treatment as desired.
[0042] In various embodiments an amount equivalent to a dosage of 10 to 500 mg/day is administered to a patient in need of such treatment. For example, the dosage can be in an amount of 10, 50, 100, or 125 to 400 mg, such as 150 to 300 mg (e.g., 175 mg, 200 mg, 225 mg, or 250 mg).
[0043] Generally, treatment continues for at least one week and can continue for several years or life-long as needed to control the subject's symptoms.
Administration and formulations.
[0044] In various embodiments the pharmaceutical compositions can be administered to the subject (e.g., patient) by any, or a combination, of several routes, such as oral, intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary, transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal, intramuscular, or long term depot preparation. In certain embodiments solid compositions for oral administration can contain suitable carriers or excipients, such as corn starch, gelatin, lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginic acid, or ingredients for controlled slow release. Disintegrators that can be used include, without limitation, micro-crystalline cellulose, corn starch, sodium starch glycolate and alginic acid. Tablet binders that can be used include, without limitation, acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.
[0045] In various embodiments liquid compositions for oral administration prepared in water or other aqueous vehicles can include solutions, emulsions, syrups, and elixirs containing, together with the active compound(s), wetting agents, sweeteners, coloring agents, and flavoring agents. Various liquid and powder compositions can be prepared by conventional methods for inhalation into the lungs of the patient to be treated.
[0046] In certain embodiments injectable compositions can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injections, the compounds may be administered by the drip method, whereby a pharmaceutical composition containing the active compound(s) and a physiologically acceptable excipient is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution or other suitable excipients. For intramuscular preparations, a sterile composition of a suitable soluble salt form of the compound can be dissolved and administered in a pharmaceutical excipient such as Water- for- Injection, 0.9% saline, or 5% glucose solution, or depot forms of the compounds (e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved in sesame oil. Alternatively, the pharmaceutical composition can be formulated as a chewing gum, lollipop, or the like.
[0047] In various embodiments combined formulations are contemplated. In certain embodiments such formulations contain at least two of the following three active agent(s): (i) an NMDA (N-methyl-D-aspartate)-Enhancer, and/or (ii) a glycine transporter inhibitor, and/or (iii) a D-amino Acid Oxidase Inhibitor (DAAOI). In certain embodiments all three active agent(s) are present in a single formulation. In combined formulations the different components can be segregated, for example, in different layers of a tablet, in different microbeads/microcapsules, and the like. In certain embodiments two of more of the active agents are intermixed and/or suspended, e.g., in a single excipient. Typically the different active agent(s) will be provided each in a therapeutically effective dose. D-amino Acid Oxidase Inhibitor (DAAOI)
[0048] D-amino Acid Oxidase Inhibitors (DAAOIs) suitable for use in the methods of the present invention are well known to those of skill in the art. Suitable DAAOIs include, for example, but are not limited to 2-oxo-3-pentynoate; Aminoguanidine (Guanylhydrazine; Carbamimidic hydrazide; Pimagedine; GER 11;
Hydrazinecarboximidamide) or hydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt, nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, PABA, Vitamin Bx, Vitamin Hl); Methylglyoxal bis(guanylhydrazone) ( also known as: Methyl GAG; Mitoguazone;
1,114(Methylethanediylidene)dinitrilo)diguanidine; Hydrazinecarboximidamide, 2,2'-(l- methyl-l,2-ethanediylidene)bis-; Pyruvaldehyde bis(amidinohydrazone); Megag; Mitoguazona [INN-Spanish] ; Guanidine, I,l1-((methylethanediylidene)dinitrilo)di-; 1,I1- ((Methylethanediylidene)dinitrilo)diguanidine); Methylglyoxal bis(guanylhydrazone), dihydrochloride; phenylglyoxal bis(guanylhydrazone) (PhGBG); glyoxal bis(guanylhydrazone) (GBG; Guanidine, l,ll-(ethanediylidenedinitrilo)di(8Cl); Hydrazinecarboximidamide, 2,2'-(l,2-ethanediylidene)bis- (9Cl)); indole-propionic (IPA, 3-(3-Indolyl)propanoic acid); 3-indole-acetic acid (Heteroauxin, IAA); Indole-3-acetic acid Sodium salt; Indole-3-acetone; Indole-3-acetamide; Indole-3-acetyl-L-aspartic acid; Indole- 3-acetyl-L-alanine; Indole-3-acetylglycine; Indole-3-acetaldehyde Sodium Bisulfite
Addition compound; Indole- 3 -carboxylic acid; Indole-3-pyruvic acid (3-(3-Indolyl)-2- oxopropanoic acid); salicylic acid (2-Hydroxybenzoic acid); salicylic acid Sodium Salt; Salicylic acid Potassium Salt; Dansyl chloride (5-(Dimethylamino)naphthalene-l-sulfonyl chloride); Dansyl fluoride (5-(Dimethylamino)naphthalene-l-sulfonyl fluoride); dansyl glycine; Alanine tetrazole; benzoic tetrazole; tetrazole; Riboflavin 5 '-pyrophosphate (RPP, 5- Phospho-alpha-D-ribosyl diphosphate, PRib-PP, P-RPP); DL-propargylglycine (DL-PG, 2- Amino-4-pentynoic acid); L-C-Propargylglycine; N-Acetyl-DL-propargylglycine; (+)- Sodium 3-hydroxybutyrate; Trigonelline Hydrochloride (l-Methylpyridinium-3- carboxylate); N-methylnicotinate; Methyl 6-methylnicotinate; Ethyl 2-methylnicotinate; Kojic acid (2-H}droxymethyl-5-hydiOxy-gamma-pyiOne, 5-Hydroxy-2- hydroxymethy 1 -4-pyranone) ; derivatives of kojic acid, such as: 6-(pyrrolidinomethyl)-kojic acid hydrochloride, 6- (morpholinomethyl) -kojic acid, 6- (diethylaminomethyl)-kojic acid hydrochloride; O-(2,4- dinitrophenyl)hydroxylamine; 2,4-dinitrophenyl glycine; Hydroxylamine Hydrochloride; Methyl-p-nitrobenzenesulfonate (Methyl 4-nitrobenzenesulfonate); Aminoethylcysteine- ketimine (AECK, Thialysine ketimine, 2H-l,4-Thiazine-5,6- dihydro-3-carboxylic acid, S- Aminoethyl-L-cysteine ketimine, 2H-l,4-Thiazine-3- carboxylic acid, 5,6-dihydro-); 1,4- thiazine derivatives; 4-Phenyl-l,4-sulfonazan (Tetrahydro-4-phenyl-4H-l,4-thiazine 1-oxide, 4H- 1,4- Thiazine, tetrahydro-4-phenyl-, 1-oxide); 1. Phenothiazine (Thiodiphenylamine, 10H- Phenothiazine, AFI-Tiazin, Agrazine, Antiverm, Dibenzo-l,4-thiazine); 3,4-Dihydro-2H-l,4- thiazine-3,5-dicarboxylic acid (3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox [BANrINN], l-((5-Nitrofurfurylidene)amino)-2- methyltetrahydro-l,4-thiazine-4,4-dioxide, 3-Methyl-4-(51-nitrofurylidene-amino)- tetrahydro-4H-l,4-thiazine- 1,1 -dioxide, BAY 2502, 4- ((5-Nitrofurfurylidene)amino)-3- methylthiomorpholine 1,1 -dioxide); 3-(l- Pyrrolidinylmethyl)-4-(5,6-dichloro-l-indancarbonyl)-tetrahydro- 1 ,4-thiazine hydrochloride (R 84760; R 84761; Thiomoφholine, 4-((5,6-dichloro-2,3-dihydro-lHinden-l-yl)carbonyl)-3-(l- pyrrolidinylmethyl)-, monohydrochloride, (R-(R*, S*))-); ketimine reduced forms; cystathionine; cystathionine ketimine; lanthionine ketimine; thiomorpholine-2-carboxylic acid; thiomorpholine-2,6-dicarboxylic acid; TMDA (l,4-Thiomorpholine-3,5-dicarboxylic acid); 1-chloro-l-nitroethane; anthranilate; Ethyl 2-aminobenzoate (ethyl anthranilate); Methyl 2-aminobenzoate (Methyl anthranilate); picolinate; Ethyl picolinate (2- (Ethoxycarbonyl)pyridine, Ethyl 2-pyridinecarboxylate, L-Leucine methyl ester, hydrochloride; L-leucine ([(S)-(+)-leucine]); Fluorodinitrobenzene (l-Fluoro-2,4- dinitrobenzene, 2,4-DNFB, Benzene, l-fluoro2,4-dinitro-, VAN); Dinitrochlorobenzene (1- Chloro-2,4-dinitrobenzene, l,3-Dinitro-4-chlorobenzene); 1,2-cyclohexanedione; Allylglycine (D-Allylglycine, 4-Pentenoic acid, 2-amino-); 2-amino-2,4-pentadienoate; 2-hydroxy-2,4- pentadienoate; 2-amino-4-keto-2-pentenoate; 2-hydroxybutyrate; Sodium 2- hydroxybutyrate; N-chloro-D-leucine; N-Acetyl-D-leucine; D-Leu (D-2-Amino-4- methylpentanoic acid); D-propargylglycine; 2-Amino-4-pentynoic acid; D,L- Propargylglycine; L-2-Amino4-pentynoic acid; Progesterone (4-Pregnene-3,20-dione); FAD (Flavin adenine dinucleotide , lH-Purin-6-amine, flavin dinucleotide, Adenosine 5'- (trihydrogen pyrophosphate), 5'-5'-ester with riboflavin); 6-OH-FAD; Phenylglyoxal (2,2- Dihydroxyacetophenone); Phenylglyoxal Monohydrate (2,2-Dihydroxyacetophenone monohydrate); Cyclothionine (Perhydro-l,4-thiazepine-3,5-dicarboxylic acid, 1,4- Hexahydrothiazepine-3,5-dicarboxylic acid, l,4-Thiazepine-3,5-dicarboxylic acid, hexahydro-); alpha-alpha'-iminodipropionic (Alanopine; 2,21-Iminodipropionic acid; L- Alanine, N-(l-carboxyethyl)-); Meso-Diaminosuccinic acid (3-Aminoaspartic acid ; Diamino succinic acid; CAS RN: 921-52-8 ); meso-2,3-Diaminosuccinic acid (CAS RN: 23220-52-2); Thiosemicarbazide (thiocarbamoyl hydrazide); Thiourea (Sulfourea; Thiocarbamide); Methylthiouracil (4(6)-Methyl-2-thiouracil, 4-Hydroxy-2-mercapto 6- methylpyrimidine); Sulphathiazole (Nl-(2-Thiazolypsulfanilamide, 4-Amino-N-2- thiazolylbenzenesulfonamide); Sulfathiazole Sodium Salt (4-Amino-N-2- thiazolylbenzenesulfonamide sodium salt); thiocyanate; 3-methylbenzyl thiocyanate; methimazole (2-mercapto-l-methylimidazole, l-methylimidazole-2- thiol); dicarboxylic hydroxyacids; 1,3-Acetonedicarboxylic acid (3-Oxoglutaric acid); D-tartaric acid ([(25,35)-(- )-tartaric acid, unnatural tartaric acid]); L-tartaric acid ( [(2R,3R)-(+)-tartaric acid, natural tartaric acid]); DL-tartaric acid; potassium tartrate; D-malic acid; [(R)-(+)-malic acid, (R)- (+) -hydroxy succinic acid]; L-malic acid; [(S)-(-)-malic acid, (S)-(-)-hydroxysuccinic acid]; DL-Malic acid (DL-hydroxysuccinic acid); Alpha-keto acids that are analogues of the amino acids alanine, leucine, phenylanaline, phenylglycine, tyrosine, serine, aspartate, and salts and derivatives thereof; pyruvic acid (2-Oxopropionic acid, alpha- Ketopropionic acid); sodium pyruvate; Pyruvic acid methyl ester (methyl pyruvate); Phenylpyruvic acid; Calcium phenylpyruvate (calcium pyruvate); Phenylpyruvic acid Sodium salt (Sodium phenylpyruvate); 4-hydroxyphenyl pyruvic acid; sodium alpha-ketoisovaleric acid (3- Methyl- 2-oxobutyric acid Sodium salt, 3- Methyl-2-oxobutanoic acid sodium salt, a- Ketoisovaleric acid Sodium salt; Ketovaline Sodium salt); benzoylformic acid (a- Oxophenylacetic acid, Phenylglyoxylic acid); 4-methylthio-2-oxopentanoic acid; 4-Methyl- 2-oxopentanoic acid (4-Methyl-2-oxovaleric acid; alpha-Ketoisocaproic acid; ; 4-methylthio- 2-oxybutanoic acid; 2-oxybutanoic acid (hydroxybutyrate; 2-Hydroxybutyric acid; alpha- Hydroxy-nbutyric acid; DL-alpha-Hydroxybutyric acid Sodium Salt (sodium (±)-2-
Hydroxybutyrate); Indole-3-pyruvic acid (alpha- Keto analogue of tryptophan ); The reaction product between cysteamine and bromopyruvate; cysteamine (2-Aminoethanethiol; 2- Mercaptoethylamine); pantetheine; 5-adenosylmethionine; Ethyl bromopyruvate; Methyl bromopyruvate; Bromopyruvate; and 5-S-Cysteinyldopamine {see, e.g., PCT Publication WO 03/047558 and US Patent Publication No: 20030185754 1, which is incorporated herein by reference. [0049] In certain embodiments preferred DAAOIs include, but are not limited to benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, aminoethylcysteine-ketimine, indole-2-carboxylic acids {see, e.g., PCT Publication WO 03/039540 which is incorporated herein by reference), and benzo[d]isoxazol-3-ol derivatives {see, e.g., U.S. Patent 7,166,725, which is incorporated herein by reference), and the like.
NMDA enhancer
[0050] NMDA enhancers suitable for use in the methods of the present invention are well known to those of skill in the art. Suitable NMDA enhancers include, for example, but are not limited to D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D- alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D-cycloserine, N-methylglycine, a salt of N- methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, , N5N- dimethylglycine, a salt of N,N-dimethylglycine, an ester of N,N-dimethylglycine, an alkylated N,N-dimethylglycine, and N,N,N-trimethylglycine.
[0051] In certain embodiments the composition is substantially free of D- cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D-cycloserine.
Glycine transporter inhibitor.
[0052] Glycine transporter inhibitors suitable for use in the methods of the present invention are well known to those of skill in the art. Suitable glycine transporter inhibitors include, but are not limited to sarcosine (N-methyl glycine), N-[3-(4'-fluorophenyl)-3-(4'- phenylphenoxy)propyl]sarcosine, (+)N[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy- )propyl] sarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compunds {see, e.g., WO/2005/094514, which is incorporated herein by reference). Other glycine transporter inhibitors include, but are not limited to N-{3-[5-Cyano-l-(4- fluorophenyl)- l,3-dihydroisobenzofuran-l-yl]-l -propyl }gl ycine ethyl ester, N-{3-[5- Cyano- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine ethyl ester, N-{3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}gl ycine, N- { 3- [5-Cyano-l -(4-fluorophenyl)- l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N - methylglycine, N- { 3- [ 1 -(3-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methylg lycine, N- { 3-[ 1 -(3-trifluoromethylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl } - N-methylglycine, N- { 3-[ 1 -(3-trifluoromethylphenyl)- 1 ,3-dihydroisobenzofuran- 1 - yl] - 1 -propyl } - N-methyl( 1 -ethyl)glycine, N- { 3 - [ 1 -(4-methylphenyl)- 1 ,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylg lycine, N- { 3- [ 1 -(4-fluorophenyl)- 1 ,3- dihydroisobenzofuran-l-yl]-l -propyl} -N-methylg lycine, N- { 3- [1 -(4-fluorophenyl)- 1,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methyla lanine, N- { 3-[ 1 -(4-fluorophenyl)- 1 ,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methyl( 1 -ethyl)glycine, N- { 3 - [4-chloro- 1 -(3- methyl-4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [4-chloro- 1 -(4-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5-chloro-l -(4-chlorophenyl)- l,3-dihydroisobenzofuran-l-yl]-l -propyl}- N- methylalanine, N- {3- [6-chloro- l-(3-methyl-4-fluorophenyl)-l,3-dihydroisobenzofuran-l- yl] - 1 -propyl } -N-methylglycine, N- { 3- [6-chloro- 1 -(4-chlorophenyl)- 1,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [6-chloro- 1 -(4- methylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [6- chloro- 1 -(4-methoxyphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [5-fluoro-l -(4-chlorophenyl)- l,3-dihydroisobenzofuran-l-yl]-l -propyl}- N- methylglycine, N-{3-[5-fluoro-l-(4-methoxyphenyl)-l,3-dihydroisobenzofuran-l-yl]-l- propyl} -N-methylglycine, N-{3-[5-trifluoromethyl-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [5-trifluoromethyl- 1 -(4- fluorophenyl)- 1, 3 -dihydroisobenzofuran-l-yl]-l -propyl }-N-methylalanine, N-{3-[5-cyano- 1 -(3-methyl-4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl } -N-methylglycine, N-{3-[5-cyano-l-(4-cyanophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}-N- methylalanine, N-{3-[5-cyano-l-(4-methoxyphenyl)-l,3-dihydroisobenzofuran-l-yl]-l- propyl}- N-methylglycine, N-{3-[5-cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l- yl]-l -propyl} -N -methylglycine, N- {2- [5-cyano-l -(4-fluorophenyl)- 1, 3- dihydroisobenzofuran-1-yl] ethyl} -N-met hylglycine, N-{3-[5-Chloro-l-(4-chloro-phenyl)- indan- 1 -yl] -propyl } -N-methylglycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] - propyl }-N-methylalanine, N-{3-[3-cyclo-l-(4-methylphenyl)-l,3-dihydroisobenzofuran-l- yl]-l -propyl} -N -methylglycine, N-[3-(3,3-Dimethyl-l-phenyl-l,3-dihydro- benzo[c] thiophen- 1 -yl)-propyl] -N-me thylglycine, N- [3-(3,3-Dimethyl- 1 -phenyl- 1,3- dihydro-benzo[c]thiophen-l-yl)-propyl]-N-me thylalanine, N-{3-[l-(4-Fluoro-phenyl)-3- dimethyl- 1,3-dihydro-isobenzofuran-l-yl] -propyl }-N-methylglycine, N-{3-[5-Bromo-l-(4- chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine, N- { 2- [ 1 -(4- Chloro-phenyl)-3,3-dimethyl-l,3-dihydro-isobenzofuran-l-yl]-ethy l}-N-methylglycine, N- [3-(3-methyl-l -phenyl- lH-inden-l-yl)-propyl]-N-methylglycine, N-[3-(5-Chloro-l- thiophen-2-yl-l,3-dihydro-isobenzofuran-l-yl)-propyl]-N-me thylglycine, N-[3-(5-Chloro- l-thiophen-2-yl-l,3-dihydro-isobenzofuran-l-yl)-propyl]-N-me thyl(l-ethyl)-glycine, N-[3- (3-methyl-l -phenyl- l,3-dihydro-isobenzofuran-l-yl)-propyl]-N-methylala nine, N-[3-(3- methyl- 1 -phenyl- 1 ,3-dihydro-isobenzofuran- 1 -yl)-propyl] -N-methyl( 1 - ethyl)-glycine, N- [3-(3,3-Dimethyl-l-phenyl-l,3-dihydro-isobenzofuran-l-yl)-ethyl]-N-methyl alanine, N-[3- (3,3-Dimethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)-ethy I]-N- methylalanine, N-[3-(3,3-Dimethyl-l-phenyl-l,3-dihydro-isobenzofuran-l-yl)-ethyl]-N- methyl -(l-ethyl)glycine, N-[3-(3,3-Dimethyl-l-(4-fluoro-phenyl)-l,3-dihydro- isobenzofuran-l-yl)-ethy l]-N-methyl-(l-ethyl)glycine, N-[3-(3,3-Diethyl-l -phenyl- 1, 3- dihydro-isobenzofuran-l-yl)-propyl]-N-methyl alanine, N-[3-(3,3-Diethyl-l-(4-chloro- phenyl)-l,3-dihydro-isobenzofuran-l-yl)-propy l]-N-methylalanine, N-[3-(3,3-Diethyl-l-(4- chloro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)-propy l]-N-methylglycine, N-[3-(l-phenyl- l,3-dihydro-benzo[c]thiophen-l-yl)-propyl]-N-methylalanine, N-{3-[l-(4-Chloro-phenyl)- 3,3-dimethyl-indan-l-yl]-propyl}-N-methylglycine, N-{3-[l-(4-Chloro-phenyl)-3,3-diethyl- 1 ,3-dihydro-isobenzofuran- 1 -yl] -propy 1 } -N-methyl-alanine, N- [2-(3 -methyl- 1 -phenyl- indan- l-yl)-ethyl] -amino }-N-methyl alanine, N-[3-(l-phenyl-(lH)-inden-l-yl)-propyl]-N- methyl-alanine, N- { 3- [ 1 -(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)- 1 ,3-dihydro- isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)- indan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] - propyl} -N-methyl-alanine, N-{3-[l-(4-chloro-phenyl)-5-(4-trifluoromethyl-phenyl)-l,3- dihydro-isobenzo furan- 1 -yl] -ethyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5-(4- methyl-phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4- Chloro-phenyl)-5-(4-methoxy-phenyl)-l,3-dihydro-isobenzofuran-l- yl] -ethyl} -N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2-thiophenyl)-l,3-dihydro-isobenzofuran-l-yl]- ethyl }-N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-methyl-phenyl)-l,3-dihydro- isobenzofuran- 1 -y 1] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5 -(4-methoxy- phenyl)- 1 ,3-dihydro-isobenzofuran- 1 - yl] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-chloro- phenyl)-5-(4-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-l,3-dihydro-isobenzofuran-l-y I]- ethyl} -N-methyl-glycine, N-{2-[l-(4-Chloro-phenyl)-5-(5-chloro-thiophen-2-yl)-l,3- dihydro-isobenzofu ran- 1-yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3- methyl-phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4- Chloro-phenyl)-5-(2-methyl-phenyl)-l,3-dihydro-isobenzofuran-l-y 1] -ethyl }-N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1- yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-chloro-phenyl)-5-(3-trifluoromethyl -phenyl)- 1,3- dihydro-isobenzo furan- 1 -yl] -ethyl } -N-methyl-glycine, N- { 3- [ 1 -(4-chloro-phenyl)-5-(3 - trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-l,3-dihydro-isobenzofuran - 1-yl] -ethyl} -N- methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-l,3-dihydro- isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5 -(3-methyl- phenyl)- 1 ,3-dihydro-isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro- phenyl)-5-(2-methyl -phenyl)- 1,3-dihydro-isobenzofuran- 1-y l] -propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1-yl]- propyl} -N-methyl-glycine, N- {3-[l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)- 1,3- dihydro-isobenzofuran -1-yl] -propyl} -N-methyl-glycine, and N-{3-[l-(4-chloro-phenyl)-5- (2-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine (see, e.g., U.S. Patent 6,921,774, which is incorporated herein by reference), or other non glycine-, N-methylglycine- structurally based inhibitors (see, e.g., Harsing et al. (2006) Current Medicinal Chemistry, 13: 1017-1104)
Additional active agents.
[0053] In certain embodiments the methods can involve administering additional therapeutic agents in conjunction with the agents described above. Similarly, the compositions can further comprise such additional therapeutic agents. Illustrative additional therapeutic agents include, but are not limited to antipsychotics, antidepressants, phsychostimulants, mood stablizers, anxiolytics, Alzheimer's disease therapeutics and other psychotropics.
[0054] In certain embodiments additional therapeutic agents include, but are not limited to, Diazepam, Bromazepam, Prazepam, Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Risperdal Consta, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Citalopram, S-Citalopram, Clomipramine, , Desipramine, Doxepin, Duloxetine, Milnacipran, Fluoxetine, Fluvoxamine, Imipramine, Isocarboxazid, Lamatrogine, Lithium, Topiramate, Gabapentin, Carbamazepine, Oxacarbazepine, Valporate, Maprotiline, Memantine, Mirtazapine, Brofaromine, Gepirone, Moclobemide, Physostigmine,, Nicotine, Huperzine Alpha, vitamine C, vitamine E,
Carotenoids, Ginkgo Biloba, Statins, Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Selegiline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Velafaxine XR, Amphetamine, Methylphenidate,Metadate-CD, Modafinil, Adderall, Adderall XR, Dexedrine, Dexedrine Spansules, Desoxyn, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Rivastigmine,
Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, Ziprasidone, aripiprazole, Paliperidone, and the like.
Compound formulations. [0055] In certain embodiments, the agents described herein are administered separately, either simultaneously or sequentially. The agents are commercially available in suitable pharmaceutically acceptable formulations.
[0056] In certain embodiments, however, the agents are provided as a combined formulations for administration by any of a variety of modalities including, but not limited to oral administration, rectal administration, injection, transdermal administration, subcutaneous depot administration, transdermal administration, and the like. Methods of preparing combined formulations are well known to those of skill in the art (see, e.g., Remington's Pharmaceutical Science, 15th ed., Mack Publishing Company, Easton, Pennsylvania (1980), Remington: The Science and Practice of Pharmacy, 21st Ed. 2005, Lippincott Williams & Wilkins, and the like). [0057] For example, oral therapeutic administration, the active agent(s) inhibitor may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. In wafer formulations, for example, different layers comprising the wafer can contain different agents. Similarly time-release capsules can comprise multiple active agents. Such compositions and preparations are typically formulated to deliver the desired concentration of agent(s) over the desired time period.
Kits
[0058] In another embodiment this invention provides kits treating (e.g., mitigating one or more symptoms of) a neuropsychiatric disorder. The kits preferably comprise a container or containers containing the combinations of active agents described herein, either a separate formulations or as a single "combined" formulation. The agent(s) can be provided in a unit dosage formulation (e.g. suppository, tablet, caplet, patch, etc.) and/or may be optionally combined with one or more pharmaceutically acceptable excipients.
[0059] In addition, the kits optionally include labeling and/or instructional materials providing directions (i.e., protocols) for the practice of the methods or use of the
"therapeutics" or "prophylactics" of this invention. Preferred instructional materials describe the use of combinations of agents as described herein to mitigate symptom(s) of a neuropsychiatric disorder and/or to prevent the onset or increase of one or more of such symptoms in an individual at risk for such a disorder. The instructional materials can also, optionally, teach preferred dosages/therapeutic regiment, counter indications and the like.
[0060] While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
EXAMPLES
[0061] The following examples are offered to illustrate, but not to limit the claimed invention.
Example 1
Introduction
[0062] Treatment by the agents enhancing N-methyl-D-aspartate neurotransmission have gained attention as an alternative for patients not responding to available psychotropics including antipsychotic medication. However, the efficacy of the individual NMDA- enhancement is limited at typical dosages. We believe a combination of NMDA-enhancing agents will render better clinical efficacy than an individual agent alone. To evaluate this hypothesis, we applied the combinational strategy in the best accepted neurophysiological model of schizophrenia in rodents, startle habituation and prepulse inhibition (PPI). [0063] The startle response is comprised of a constellation of reflexes elicited by sudden relatively intense stimuli. It offers many advantages as a behavioral measure of central nervous system activity when elicited by acoustic (noise burst), electrical (cutaneous), tactile (air puff), or visual (light flash) stimuli. The startle reflex has served as a tool for studying fundamental properties of nervous function of complex behavioral states and cognitive processes.
[0064] The forebrain modulates several forms of startle plasticity including the habituation and PPI. Changes in startle magnitude through repeated stimulus presentations- habituation and sensitization-represent the simple forms of learning. Quantification of startle habituation and sensitization in rodent has direct physiological relevance to human CNS function. In fact, the most well accepted animal physiology models for schizophrenia are startle habituation and PPI.
[0065] Therefore, to test the hypothesis that combinational NMDA-enhancing agent treatment has better efficacy than individual agent alone, we tested startle habituation and PPI in animals receiving single NMDA-enhancing agents, sarcosine (N-methylglycine, a glycine transporter- 1 inhibitor), benzoate (a D-amino acid oxidase inhibitor), the combination of both agents or the vehicle. We also tested the hypothesis in a well accepted pharmacological model of schizophrenia, amphetamine-disruption of startle habituation and PPI.
Method
[0066] For the systematic investigation of the neurobiological systems that modulate sensorimotor inhibition, startle magnitude was investigated. Startle magnitude is reduced when the pulse stimulus is preceded 30 to 500 msec by a weak prepulse. This inhibition ("gating") of a motor response elicited by a weak sensory event, termed PPI, provides an operational measure of sensorimotor gating. Prepulse stimuli of 3, 6, or 12 dB above the 70 dB background noise inhibit the startle response elicited by 120-dB pulse stimuli. Prestimuli used in intramodal studies of sensorimotor gating of acoustic startle are by the delivery of a discrete acoustic prepulse several msec before the startle pulse, with an intensity below startle threshold. Holding the interval between the prepulse and pulse stimuli constant at 100 msec typically yields suitable levels of PPI, ranging from 20% to 80% inhibition.
[0067] For habituation, we present six trials of a single acoustic stimulus to each mouse. To provide a consistent acoustic environment and to mask external noises, maintain a continuous background noise level of 70 dB within each startle chamber. We collected the peak or average response from each mouse on each of six trials, then averaged the six responses together for each mouse. Five more trials at the end of PPI were done. The results were averaged and compared to the original six trials. The difference of startle responses between the initial six and the last five trials were considered the amount of habituation. Analyses include the independent variable (e.g., vehicle or drug treatment) as a factor in analyses of variance (ANOVA) on the dependent measures (difference of the average of the first and last six trials).
[0068] There were a total of 36 trials in the experiments. The three prepulse stimuli were with a duration of 20 msec. For each mouse the following metrics were determined: 1) Average response magnitude on pulse-only trials 1 to 6 and 32 to 36; 2)Average response magnitude in each of the four trial types between trials 7 and 31 inclusively (i.e., ten pulse- only trials and five each of the three prepulse variations). The first block of pulse-only trials were analyzed as measures of startle reactivity. The first and last blocks of pulse-only trials were analyzed together in a repeated measure ANOVA to assess habituation of acoustic startle across the test session. The four values (3, 6, or 12 dB above background) derived from trials 7 to 31 were used to assess PPI which was calculated for each mouse as: Percentage score: PPI = 100 % x { [pulse-only units -(prepulse + pulse units)]/(pulse- onlyunits) } .
[0069] Male 129 SVE adult mice were first tested at baseline. Four groups of 10 mice each were treated with sarcosine (200 mg/kg), benzoate (100 mg/kg), a combination of both sarcosine and benzoate (same doses as the individual treatment), or with vehicle for one week before the test. The mice continued to receive the drug until one week later when amphetamatine (10 mg/kg) was administered 30 minutes before the experiments.
Results
[0070] We found that there was no difference in the habituation at baseline (when no drug had been administered) across the groups (Figure 1, left). But combination treatments induce a stronger habituation effect than benzoate or sarcosine treatment alone (Figure 1, middle). The same trend of habituation (combination treatment >benzoate>sarcosine) was evident when amphetamine was administered and disrupted the habituation (Figure 1, right). The combination is better than the individual treatment in ehancing the habituation (Figure 1, middle). The combination treatment corrected the amphetamine-induced disruption of habituation back to normal state while single treatment of NMG or benzoate only partially correct the deficit (Figure 1, right).
[0071] For PPI, we found that in general stronger prepulse inhibited pulse response more (inhibition of 525 Hz>487Hz>468Hz) (Figure T). Amphetamine disrupted the inhibition in all treatments. This disruption by amphetamine is most pronounced in vehicle- treated mice (second left column of each prepulse group), partially corrected by either sarcosine (NMG) or benzoate (fourth and sixth left column of each prepulse group) and was best corrected by the combination treatment (far right column in each prepulse group). Conclusion
[0072] In the most accepted animal model of schizophrenia, which tests the sensory gating, we found that combination treatment improve the startle habituation and PPI significantly more than the individual agent alone. [0073] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

CLAIMSWhat is claimed is:
1. A pharmaceutical composition comprising: a D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer and/or a glycine transporter inhibitor.
2. The composition of claim 1, wherein said composition comprises: a D-amino Acid Oxidase Inhibitor (DAAOI); and an NMDA enhancer.
3. The composition of claim 1, wherein said composition comprises: a D-amino Acid Oxidase Inhibitor (DAAOI); and a glycine transporter inhibitor.
4. The composition of claim 1, wherein said composition comprises: a D-amino Acid Oxidase Inhibitor (DAAOI); an NMDA enhancer; and a glycine transporter inhibitor.
5. The composition according to any one of claims 1-4, wherein said D- amino Acid Oxidase Inhibitor is selected from the group consisting of 2-oxo-3-pentynoate; Aminoguanidine (Guanylhydrazine; Carbamimidic hydrazide; Pimagedine; GER 11; Hydrazinecarboximidamide) or hydrochloride salt (Guanylhydrazine hydrochloride), bicarbonate salt, nitrate salt, sulfate (2:1) salt, sulfate (1:1) salt, and hemisulfate salt thereof; benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p- aminobenzoate, PABA, Vitamin Bx, Vitamin Hl); Methylglyoxal bis(guanylhydrazone) ( also known as: Methyl GAG; Mitoguazone; 1,114(Methylethanediylidene)dinitrilo)diguanidine; Hydrazinecarboximidamide, 2,2'-(l- methyl -l,2-ethanediylidene)bis-; Pyruvaldehyde bis(amidinohydrazone); Megag;
Mitoguazona [INN-Spanish] ; Guanidine, I,l1-((methylethanediylidene)dinitrilo)di-; 1,I1- ((Methylethanediylidene)dinitrilo)diguanidine); Methylglyoxal bis(guanylhydrazone), dihydrochloride; phenylglyoxal bis(guanylhydrazone) (PhGBG); glyoxal bis(guanylhydrazone) (GBG; Guanidine, l,ll-(ethanediylidenedinitrilo)di(8Cl); Hydrazinecarboximidamide, 2,2'-(l,2-ethanediylidene)bis- (9Cl)); indole-propionic (IPA, 3-(3-Indolyl)propanoic acid); 3 -indole- acetic acid (Heteroauxin, IAA); Indole-3-acetic acid Sodium salt; Indole-3-acetone; Indole-3-acetamide; Indole-3-acetyl-L-aspartic acid; Indole- 3-acetyl-L-alanine; Indole-3-acetylglycine; Indole-3-acetaldehyde Sodium Bisulfite Addition compound; Indole-3-carboxylic acid; Indole-3-pyruvic acid (3-(3-Indolyl)-2- oxopropanoic acid); salicylic acid (2-Hydroxybenzoic acid); salicylic acid Sodium Salt; Salicylic acid Potassium Salt; Dansyl chloride (5-(Dimethylamino)naphthalene-l-sulfbnyl chloride); Dansyl fluoride (5-(Dimethylamino)naphthalene-l-sulfonyl fluoride); dansyl glycine; Alanine tetrazole; benzoic tetrazole; tetrazole; Riboflavin 5 '-pyrophosphate (RPP, 5- Phospho-alpha-D-ribosyl diphosphate, PRib-PP, P-RPP); DL-propargylglycine (DL-PG, 2- Amino-4-pentynoic acid); L-C-Propargylglycine; N-Acetyl-DL-propargylglycine; (+)- Sodium 3-hydroxybutyrate; Trigonelline Hydrochloride (l-Methylpyridinium-3- carboxylate); N-methylnicotinate; Methyl 6-methylnicotinate; Ethyl 2-methylnicotinate; Kojic acid (2-H}droxymethyl-5-hydiOxy-gamma-pyiOne, 5-Hydroxy-2- hydroxymethy 1 -4-pyranone) ; derivatives of kojic acid, such as: 6-(pyrrolidinomethyl)-kojic acid hydrochloride, 6- (morpholinomethyl) -kojic acid, 6- (diethylaminomethyl)-kojic acid hydrochloride; O-(2,4- dinitrophenyl)hydroxylamine; 2,4-dinitrophenyl glycine; Hydroxylamine Hydrochloride; Methyl-p-nitrobenzenesulfonate (Methyl 4-nitrobenzenesulfonate); Aminoethylcysteine- ketimine (AECK, Thialysine ketimine, 2H-l,4-Thiazine-5,6- dihydro-3-carboxylic acid, S- Aminoethyl-L-cysteine ketimine, 2H-l,4-Thiazine-3- carboxylic acid, 5,6-dihydro-); 1,4- thiazine derivatives; 4-Phenyl-l,4-sulfonazan (Tetrahydro-4-phenyl-4H-l,4-thiazine 1 -oxide, 4H- 1,4- Thiazine, tetrahydro-4-phenyl-, 1-oxide); 1. Phenothiazine (Thiodiphenylamine, 10H- Phenothiazine, AFI-Tiazin, Agrazine, Antiverm, Dibenzo-l,4-thiazine); 3,4-Dihydro-2H-l,4- thiazine-3,5-dicarboxylic acid (3,4-Dhtca, CAS#86360-62-5); Nifurtimox (Nifurtimox
[B AN:INN] , 1 -((5-Nitrofurfurylidene)amino)-2- methyltetrahydro- 1 ,4-thiazine-4,4-dioxide, 3-Methyl-4-(51-nitrofurylidene-amino)- tetrahydro-4H-l,4-thiazine- 1,1 -dioxide, BAY 2502, 4- ((5-Nitrofurfurylidene)amino)-3- methylthiomorpholine 1,1 -dioxide); 3-(l- Pyrrolidinylmethyl)-4-(5,6-dichloro-l-indancarbonyl)-tetrahydro- 1 ,4-thiazine hydrochloride (R 84760; R 84761; Thiomorpholine, 4-((5,6-dichloro-2,3-dihydro-lHinden-l-yl)carbonyl)-3-(l- pyrrolidinylmethyl)-, monohydrochloride, (R-(R*, S*))-); ketimine reduced forms; cystathionine; cystathionine ketimine; lanthionine ketimine; thiomorpholine-2-carboxylic acid; thiomorpholine-2,6-dicarboxylic acid; TMDA (l,4-Thiomorpholine-3,5-dicarboxylic acid); 1-chloro-l-nitroethane; anthranilate; Ethyl 2-aminobenzoate (ethyl anthranilate); Methyl 2-aminobenzoate (Methyl anthranilate); picolinate; Ethyl picolinate (2- (Ethoxycarbonyl)pyridine, Ethyl 2-pyridinecarboxylate, L-Leucine methyl ester, hydrochloride; L-leucine ([(S)-(+)-leucine]); Fluorodinitrobenzene (l-Fluoro-2,4- dinitrobenzene, 2,4-DNFB, Benzene, l-fluoro2,4-dinitro-, VAN); Dinitrochlorobenzene (1- Chloro-2,4-dinitrobenzene, l,3-Dinitro-4-chlorobenzene); 1,2-cyclohexanedione; Allylglycine (D-Allylglycine, 4-Pentenoic acid, 2-amino-); 2-amino-2,4-pentadienoate; 2-hydroxy-2,4- pentadienoate; 2-amino-4-keto-2-pentenoate; 2-hydroxybutyrate; Sodium 2- hydroxybutyrate; N-chloro-D-leucine; N-Acetyl-D-leucine; D-Leu (D-2-Amino-4- methylpentanoic acid); D-propargylglycine; 2-Amino-4-pentynoic acid; D,L- Propargylglycine; L-2-Amino4-pentynoic acid; Progesterone (4-Pregnene-3,20-dione); FAD (Flavin adenine dinucleotide , lH-Purin-6-amine, flavin dinucleotide, Adenosine 5'- (trihydrogen pyrophosphate), 5'-5'-ester with riboflavin); 6-OH-FAD; Phenylglyoxal (2,2- Dihydroxyacetophenone); Phenylglyoxal Monohydrate (2,2-Dihydroxyacetophenone monohydrate); Cyclothionine (Perhydro-l,4-thiazepine-3,5-dicarboxylic acid, 1,4- Hexahydrothiazepine-3,5-dicarboxylic acid, l,4-Thiazepine-3,5-dicarboxylic acid, hexahydro-); alpha-alpha'-iminodipropionic (Alanopine; 2,21-Iminodipropionic acid; L- Alanine, N-(l-carboxyethyl)-); Meso-Diaminosuccinic acid (3-Aminoaspartic acid ; Diaminosuccinic acid; CAS RN: 921-52-8 ); meso-2,3-Diaminosuccinic acid (CAS RN: 23220-52-2); Thiosemicarbazide (thiocarbamoyl hydrazide); Thiourea (Sulfourea; Thiocarbamide); Methylthiouracil (4(6)-Methyl-2-thiouracil, 4-Hydroxy-2-mercapto 6- methylpyrimidine); Sulphathiazole (Nl-(2-Thiazolypsulfanilamide, 4-Amino-N-2- thiazolylbenzenesulfonamide); Sulfathiazole Sodium Salt (4-Amino-N-2- thiazolylbenzenesulfonamide sodium salt); thiocyanate; 3-methylbenzyl thiocyanate; methimazole (2-mercapto-l-methylimidazole, l-methylimidazole-2- thiol); dicarboxylic hydroxyacids; 1,3-Acetonedicarboxylic acid (3-Oxoglutaric acid); D-tartaric acid ([(25,35)-(- )-tartaric acid, unnatural tartaric acid]); L-tartaric acid ( [(2R,3R)-(+)-tartaric acid, natural tartaric acid]); DL-tartaric acid; potassium tartrate; D-malic acid; [(R)-(+)-malic acid, (R)- (+) -hydroxy succinic acid]; L-malic acid; [(S)-(-)-malic acid, (S)-(-)-hydroxysuccinic acid]; DL-Malic acid (DL-hydroxysuccinic acid); Alpha-keto acids that are analogues of the amino acids alanine, leucine, phenylanaline, phenylglycine, tyrosine, serine, aspartate, and salts and derivatives thereof; pyruvic acid (2-Oxopropionic acid, alpha-Ketopropionic acid); sodium pyruvate; Pyruvic acid methyl ester (methyl pyruvate); Phenylpyruvic acid; Calcium phenylpyruvate (calcium pyruvate); Phenylpyruvic acid Sodium salt (Sodium phenylpyruvate); 4-hydroxyphenyl pyruvic acid; sodium alpha-ketoisovaleric acid (3- Methyl- 2-oxobutyric acid Sodium salt, 3- Methyl-2-oxobutanoic acid sodium salt, a- Ketoisovaleric acid Sodium salt; Ketovaline Sodium salt); benzoylformic acid (a- Oxophenylacetic acid, Phenylglyoxylic acid); 4-methylthio-2-oxopentanoic acid; 4-Methyl- 2-oxopentanoic acid (4-Methyl-2-oxovaleric acid; alpha-Ketoisocaproic acid; ; 4-methylthio- 2-oxybutanoic acid; 2-oxybutanoic acid (hydroxybutyrate; 2-Hydroxybutyric acid; alpha- Hydroxy-nbutyric acid; DL-alpha-Hydroxybutyric acid Sodium Salt (sodium (±)-2-
Hydroxybutyrate); Indole-3-pyruvic acid (alpha- Keto analogue of tryptophan ); The reaction product between cysteamine and bromopyruvate; cysteamine (2-Aminoethanethiol; 2- Mercaptoethylamine); pantetheine; 5-adenosylmethionine; Ethyl bromopyruvate; Methyl bromopyruvate; Bromopyruvate; and 5-S-Cysteinyldopamine.
6. The composition according to any one of claims 1-4, wherein said D- amino Acid Oxidase Inhibitor is selected from the group consisting of benzoic acid; sodium benzoate; 2-aminobenzoate; 3-aminobenzoate; 4-aminobenzoate (p-aminobenzoate, aminoethylcysteine-ketimine, indole-2-carboxylic acids, and benzo[d]isoxazol-3-ol derivatives.
7. The composition according to any one of claims 1, 2, and 4, wherein said NMDA enhancer is selected from the group consisting of D-alanine, a salt of D- alanine, an ester of D-alanine, an alkylated D-alanine, a precursor of D-alanine, D-serine, a salt of D-serine, an alkylated D-serine, a precursor of D-serine, D-cycloserine, a salt of D- cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, an alkylated D- cycloserine, N-methylglycine, a salt of N-methylglycine, an ester of N-methylglycine, an alkylated N-methylglycine, , N,N-dimethylglycine, a salt of N,N-dimethylglycine, an ester of N,N-dimethylglycine, an alkylated N,N-dimethylglycine, and N,N,N-trimethylglycine.
8. The composition of claim 7, wherein: the composition is substantially free of D-cycloserine when the agonist is D-alanine, a salt of D-alanine, an ester of D-alanine, an alkylated D-alanine, or a precursor of D-alanine; and when the agonist is D-cycloserine, a salt of D-cycloserine, an ester of D-cycloserine, a precursor of D-cycloserine, or alkylated D-cycloserine, the pharmaceutical composition comprises an amount of the agonist equivalent to 105-500 mg of D- cycloserine.
9. The composition according to any one of claims 1, 3, and 4, wherein said glycine transporter inhibitor is selected from the group consisting of sarcosine (N- methyl glycine), N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl] sarcosine, (+)N[3-(4'- fluorophenyl)-3-(4'-phenylphenoxy-)propyl] sarcosine (NFPS), pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl piperidine compunds, N-{3-[5-Cyano-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-l-yl]-l -propyl }gl ycine ethyl ester, N-{3-[5-Cyano-l-(4- fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}-N -methylglycine ethyl ester, N- {3-[5-Cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l-propyl}gl ycine, N-{3- [5-Cyano- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine, N- { 3- [ 1 -(3-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylg lycine, N- { 3-[ 1 -(3-trifluoromethylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N- methylglycine, N- { 3- [ 1 -(3-trifluoromethylphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl}- N-methyl(l-ethyl)glycine, N-{3-[l-(4-methylphenyl)-l,3-dihydroisobenzofuran-l- yl] - 1 -propyl } -N-methylg lycine, N- { 3- [ 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylg lycine, N- { 3- [ 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl } -N-methyla lanine, N- { 3-[ 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl }-N-methyl( l-ethyl)glycine, N-{3-[4-chloro-l-(3-methyl-4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [4-chloro- 1 -(4- chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5- chloro- 1 -(4-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylalanine, N- {3-[6-chloro-l-(3-methyl-4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N- methylglycine, N- { 3- [6-chloro- 1 -(4-chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 - propyl}- N-methylglycine, N-{3-[6-chloro-l-(4-methylphenyl)-l,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [6-chloro- 1 -(4-methoxyphenyl)- 1 ,3- dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [5-fluoro- 1 -(4- chlorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5-fluoro- 1 -(4-methoxyphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N-methylglycine, N- { 3- [5-trifruoromethyl- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N- methylglycine, N- { 3- [5-trifluoromethyl- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl }-N-methylalanine, N-{3-[5-cyano-l-(3-methyl-4-fluorophenyl)-l,3- dihydroisobenzofuran- 1 -yl] - 1 - propyl } -N-methylglycine, N- { 3- [5-cyano- 1 -(4- cyanophenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N- methylalanine, N-{3-[5-cyano- 1 -(4-methoxyphenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } - N-methylglycine, N- { 3- [5-cyano- 1 -(4-fluorophenyl)- 1 ,3-dihydroisobenzofuran- 1 -yl] - 1 -propyl } -N -methylglycine, N-{2-[5-cyano-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-l-yl]ethyl} -N-met hylglycine, N- { 3- [5-Chloro-l-(4-chloro-phenyl)-indan-l-yl] -propyl} -N-methylglycine, N- {3- [5- Chloro-l-(4-chloro-phenyl)-indan-l-yl] -propyl }-N-methylalanine, N-{3-[3-cyclo-l-(4- methylphenyl)-l,3-dihydroisobenzofuran-l-yl]-l -propyl} -N -methylglycine, N-[3-(3,3- Dimethyl- 1 -phenyl- 1 ,3-dihydro-benzo[c] thiophen- 1 -yl)-propyl] -N-me thylglycine, N- [3- (3,3-Dimethyl-l-phenyl-l,3-dihydro-benzo[c]thiophen-l-yl)-propyl]-N-me thylalanine, N- {3-[l-(4-Fluoro-phenyl)-3-dimethyl-l,3-dihydro-isobenzofuran-l-yl]-propyl }-N- methylglycine, N-{3-[5-Bromo-l-(4-chlorophenyl)-l,3-dihydroisobenzofuran-l-yl]-l- propyl}-N -methylglycine, N-{2-[l-(4-Chloro-phenyl)-3,3-dimethyl-l,3-dihydro- isobenzofuran- 1 -yl] -ethy 1 } -N-methylglycine, N- [3-(3-methyl- 1 -phenyl- lH-inden- 1-yl)- propyl] -N-methylglycine, N-[3-(5-Chloro-l-thiophen-2-yl-l,3-dihydro-isobenzofuran-l-yl)- propyl]-N-me thylglycine, N-[3-(5-Chloro-l-thiophen-2-yl-l,3-dihydro-isobenzofuran-l- yl)-propyl]-N-me thyl(l-ethyl)-glycine, N- [3-(3-methyl-l -phenyl- 1, 3-dihydro- isobenzofuran-l-yl)-propyl]-N-methylala nine, N- [3-(3-methyl-l -phenyl- 1,3-dihydro- isobenzofuran-l-yl)-propyl]-N-methyl(l- ethyl)-glycine, N-[3-(3,3-Dimethyl-l-phenyl-l,3- dihydro-isobenzofuran-l-yl)-ethyl]-N-methyl alanine, N-[3-(3,3-Dimethyl-l-(4-fluoro- phenyl)-l,3-dihydro-isobenzofuran-l-yl)-ethy l]-N-methylalanine, N-[3-(3,3-Dimethyl-l- phenyl-l,3-dihydro-isobenzofuran-l-yl)-ethyl]-N-methyl -(l-ethyl)glycine, N-[3-(3,3- Dimethyl-l-(4-fluoro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)-ethy l]-N-methyl-(l- ethyl)glycine, N-[3-(3,3-Diethyl-l -phenyl- l,3-dihydro-isobenzofuran-l-yl)-propyl]-N- methyl alanine, N-[3-(3,3-Diethyl-l-(4-chloro-phenyl)-l,3-dihydro-isobenzofuran-l-yl)- propy l]-N-methylalanine, N-[3-(3,3-Diethyl-l-(4-chloro-phenyl)-l,3-dihydro- isobenzofuran-l-yl)-propy 1] -N-methylglycine, N- [3-(l -phenyl- 1,3-dihydro- benzo[c]thiophen-l-yl)-propyl]-N-methylalanine, N-{3-[l-(4-Chloro-phenyl)-3,3-dimethyl- indan-1-yl] -propyl }-N-methylglycine, N-{3-[l-(4-Chloro-phenyl)-3,3-diethyl-l,3-dihydro- isobenzofuran- 1 -yl] -propy 1 } -N-methyl-alanine, N- [2-(3-methyl- 1 -phenyl-indan- 1-yl)- ethyl] -amino } -N-methyl alanine, N- [3-( 1 -phenyl-( 1 H)-inden- 1 -yl)-propyl] -N-methyl- alanine, N-{3-[l-(4-Fluoro-phenyl)-5-(4-trifluoromethyl-phenyl)-l,3-dihydro-isobenzo furan-1-yl] -propyl }-N-methyl-glycine, N-{3-[5-Chloro-l-(4-chloro-phenyl)-indan-l-yl]- propyl } -N-methyl-glycine, N- { 3- [5-Chloro- 1 -(4-chloro-phenyl)-indan- 1 -yl] -propyl } -N- methyl-alanine, N-{3-[l-(4-chloro-phenyl)-5-(4-trifluoromethyl-phenyl)-l,3-dihydro- isobenzo furan-1-yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-methyl- phenyl)- 1,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro- phenyl)-5-(4-methoxy-phenyl)-l,3-dihydro-isobenzofuran-l- yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2-thiophenyl)-l,3-dihydro-isobenzofuran-l-yl]- ethyl}-N- methyl-glycine, N- {3- [l-(4-Chloro-phenyl)-5-(4-methyl-phenyl)- 1,3-dihydro- isobenzofuran-l-y 1] -propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-methoxy- phenyl)- 1,3-dihydro-isobenzofuran-l- yl] -propyl} -N-methyl-glycine, N-{3-[l-(4-chloro- phenyl)-5-(4-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-l,3-dihydro-isobenzofuran-l-y I]- ethyl} -N-methyl-glycine, N-{2-[l-(4-Chloro-phenyl)-5-(5-chloro-thiophen-2-yl)-l,3- dihydro-isobenzofu ran- 1-yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3- methyl-phenyl)- 1,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl-glycine, N-{3-[l-(4- Chloro-phenyl)-5-(2-methyl-phenyl)- 1,3-dihydro-isobenzofuran-l-y 1] -ethyl} -N-methyl- glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1- yl] -ethyl} -N-methyl-glycine, N-{3-[l-(4-chloro-phenyl)-5-(3-trifluoromethyl -phenyl)- 1 ,3- dihydro-isobenzo furan- 1 -yl] -ethyl } -N-methyl-glycine, N- { 3- [ 1 -(4-chloro-phenyl)-5-(3 - trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1 -yl] -propyl } -N-methyl-glycine, N- { 3- [l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-l,3-dihydro-isobenzofuran - 1-yl] -ethyl} -N- methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(4-chloro-phenyl)-l,3-dihydro- isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro-phenyl)-5 -(3-methyl- phenyl)- 1 ,3-dihydro-isobenzofuran- 1-y l] -propyl } -N-methyl-glycine, N- { 3- [ 1 -(4-Chloro- phenyl)-5-(2-methyl -phenyl)- 1,3-dihydro-isobenzofuran- 1-y l] -propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(2,5-dichloro-phenyl)-l,3-dihydro-isobenzofuran -1-yl]- propyl} -N-methyl-glycine, N-{3-[l-(4-Chloro-phenyl)-5-(3,4-dichloro-phenyl)-l,3- dihydro-isobenzofuran -1-yl] -propyl }-N-methyl-glycine, and N-{3-[l-(4-chloro-phenyl)-5- (2-trifluoromethyl-phenyl)- 1 ,3-dihydro-isobenzo furan- 1-yl] -propyl } -N-methyl-glycine.
10. The composition according to any one of claims 1-5, wherein composition further comprises an additional therapeutic agent selected from the group consisting of antipsychotics, antidepressants, phsychostimulants, mood stabilizers, anxiolytics, Alzheimer's disease therapeutics and other psychotropics.
11. The composition of claim 10, wherein said additional therapeutic agent is selected from the group consisting of Diazepam, Bromazepam, Prazepam, Chlordiazepoxide, Clobazam, Estazolam, Flurazepam, Clonazepam, Temazepam, Triazolam, Alprazolam, Midazolam, Brotizolam, Nitrazepam, Flunitrazepam, Oxazepam, Quazepam, Lorazepam, Temazepam, Triazolam, Zolpidem, Zopiclone, Zaleplon, Chlorpromazine, Thioridazine, Mesoridazine, Fluphenazine, Perphenazine, Trifluoperazine, Thiothixene, Haloperidol, Loxapine, Molindone, Clozapine, Risperidone, Olanzapine, Quetiapine, Haloperidol decanoate, Fluphenazine decanoate, Fluphenazine enanthate, Risperdal Consta, Amitriptyline, Amoxapine, Bupropion, Bupropion SR, Citalopram, S- Citalopram, Clomipramine, , Desipramine, Doxepin, Duloxetine, Milnacipran, Fluoxetine, Fluvoxamine, Imipramine, Isocarboxazid, Lamatrogine, Lithium, Topiramate, Gabapentin, Carbamazepine, Oxacarbazepine, Valporate, Maprotiline, Memantine, Mirtazapine, Brofaromine, Gepirone, Moclobemide, Physostigmine,, Nicotine, Huperzine Alpha, vitamine C, vitamine E, Carotenoids, Ginkgo Biloba, Statins, Nefazodone, Nortriptyline, Paroxetine, Phenelzine, Protriptyline, Sertraline, Selegiline, Tranylcypromine, Trazodone, Trimipramine, Venlafaxine, Velafaxine XR, Amphetamine, Methylphenidate,Metadate-CD, Modafinil, Adderall, Adderall XR, Dexedrine, Dexedrine Spansules, Desoxyn, Dextroamphetamine, Methamphetamine, Methylphenidate, Pemoline, Donepezil, Tacrine, Rivastigmine, Acetophenazine, Chlorprothixene, Droperidol, Pimozide, Butaperazine, Carphenazine, Remoxipride, Piperacetazine, Sulpiride, Ziprasidone, aripiprazole, Paliperidone, etc.
12. The composition of claim 1, wherein said composition is formulated as a unit dosage formulation.
13. The composition of claim 1, wherein the active agent(s) comprising said composition are independently formulated as salts, esters, or prodrugs.
14. The composition of claim 1, wherein said composition is formulated for administration by a route selected from the group consisting of oral administration, transdermal administration, intramuscular administration, rectal administration, intravenous administration, intrathecal administration, intraperitoneal administration, administration in a subcutaneous depot formulation, and administration as an inhalant.
15. A method of mitigating one or more symptoms of a neuropsychiatric disorder, said method comprising: administering to a subject in need thereof a D-amino Acid Oxidase
Inhibitor (DAAOI); in conjunction with an NMDA enhancer and/or a glycine transporter inhibitor.
16. The method of claim 15, wherein said method comprises: administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with an NMDA enhancer.
17. The method of claim 15, wherein said method comprises: administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with a glycine transporter inhibitor.
18. The method of claim 15, wherein said method comprises: administering a D-amino Acid Oxidase Inhibitor (DAAOI) in conjunction with an NMDA enhancer and a glycine transporter inhibitor.
19. The method of claim 15, wherein said method comprises: administering a NMDA enhancer in conjunction with a glycine transporter inhibitor.
20. The method of claim 15, wherein said method comprises administering a composition according to any one of claims 1-14.
21. The method of claim 15, wherein said neuropsychiatric disorder is schizophrenia.
22. The method of claim 15, wherein said neuropsychiatry disorder is not schizophrenia.
23. The method of claim 15, wherein said neuropsychiatric disorder is Alzheimer's disease.
24. The method of claim 15, wherein said neuropsychiatric disorder is autism.
25. The method of claim 15, wherein said neuropsychiatric disorder is depression.
26. The method of claim 15, wherein said neuropsychiatric disorder is benign forgetfulness.
27. The method of claim 15, wherein said neurpsychiatric disorder is a childhood learning disorder.
28. The method of claim 15, wherein said neuropsychiatric disorder is attention deficit disorder.
29. The method of claim 15, wherein said neuropsychiatric disorder is close head injury.
30. The method of claim 15, wherein said neuropsychiatric disorder is anxiety disorders including obsessive compulsive disorder.
31. The method of claim 15, wherein said neuropsychiatric disorder is close post-traumatic stress disorder.
32. The method of claim 15, wherein said neuropsychiatric disorder is substance abuse.
33. The method of claim 15, wherein said D-amino Acid Oxidase Inhibitor (DAAOI) is administered in a dosage ranging from 1 mg to about 150 g.
34. The method of claim 15, wherein said NMDA enhancer is administered at a dosage ranging from about 20 mg to about 150 g.
35. The method of claim 15, wherein said glycine transporter inhibitor is administered at a dosage ranging from 10 mg to 50 g.
36. A method of mitigating one or more symptoms of a neuropsychiatric disorder, said method comprising administering to a subject in need thereof a D-amino Acid Oxidase Inhibitor (DAAOI) at sufficient dosage to mitigate one or more symptoms of a neuropsychiatric disorder.
37. The use of a combination of an NMDA enhancer and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder.
38. The use of a combination of D-amino Acid Oxidase Inhibitor
(DAAOI); and an NMDA enhancer in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder.
39. The use of a combination of a D-amino Acid Oxidase Inhibitor
(DAAOI); and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder.
40. The use of a combination of a D-amino Acid Oxidase Inhibitor (DAAOI), an NMDA enhancer; and a glycine transporter inhibitor in the manufacture of a medicament for the treatment or prophylaxis of a neuropsychiatric disorder.
PCT/US2008/071632 2007-07-30 2008-07-30 Combination treatment of nmda (n-methyl-d-aspartate)-enhancer, glycine transporter inhibitor, d-amino acid oxidase inhibitor (daaoi) for neuropsychiatric disorders WO2009018368A1 (en)

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