EP1778244A1 - Use of n-desmethylclozapine to treat human neuropsychiatric disease - Google Patents

Use of n-desmethylclozapine to treat human neuropsychiatric disease

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Publication number
EP1778244A1
EP1778244A1 EP05802835A EP05802835A EP1778244A1 EP 1778244 A1 EP1778244 A1 EP 1778244A1 EP 05802835 A EP05802835 A EP 05802835A EP 05802835 A EP05802835 A EP 05802835A EP 1778244 A1 EP1778244 A1 EP 1778244A1
Authority
EP
European Patent Office
Prior art keywords
clozapine
desmethylclozapine
ndmc
symptoms
subject
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05802835A
Other languages
German (de)
English (en)
French (fr)
Inventor
David M. Weiner
Mark R. Brann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Acadia Pharmaceuticals Inc
Original Assignee
Acadia Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/913,117 external-priority patent/US20050085463A1/en
Priority claimed from US11/098,892 external-priority patent/US20050250767A1/en
Application filed by Acadia Pharmaceuticals Inc filed Critical Acadia Pharmaceuticals Inc
Publication of EP1778244A1 publication Critical patent/EP1778244A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to the discovery of potent muscarinic receptor agonist properties of the dibenzodiazepine compound N-desmethylclozapine, 8- chloro-l l-(l-piperazinyl)-5H-dibenzo[b,e][l,4]diazepine, which supports the clinical use of this drug as a superior therapeutic agent for the treatment of pain, glaucoma, dementia, affective disease, and psychosis.
  • Muscarinic receptors comprise a family of five (M1-M5) transmembrane proteins that mediate slow, modulatory signalling in cells and tissues expressing these genes. Muscarinic receptors are the targets of a number of therapeutically useful agents (1, 2). Peripherally, muscarinic receptors mediate the actions of acetylcholine in the parasympathetic nervous system. Peripherally acting muscarinic receptor agonists are therapuetically useful in lowering intra-ocular pressure in patients with glaucoma (3). Compounds that potentiate the central actions of acetylcholine as well as centrally acting muscarinic receptor agonists have both demonstrated clinical utility in the treatment of a number of neuropsychiatric diseases (1, 2, 4-7).
  • acetylcholine The actions of acetylcholine are terminated by degradation of the molecule by acetylcholinesterase enzymes. Inhibition of these enzymes within the central nervous system leads to increased concentrations of acetylcholine at muscarinic receptors.
  • acetylcholinesterase inhibitors have been developed and are in routine clinical use as cognitive enhancing agents in dementia (4).
  • muscarinic receptor agonists have been the subject of clinical testing.
  • One of these, Xanomeline has been shown to possess efficacy in controlling psychosis and related behavioral disturbances observed in Alzheimer's Disease patients (5).
  • xanomeline is efficacious in treating schizophrenia (6).
  • compounds with muscarinic receptor agonist properties are likely to be efficacious in treating the behavioral disturbances common to neurodegenerative disease such as Alzheimers Disease and as antipsychotics to treat human psychoses, but only if they are tolerated in these patient populations.
  • muscarinic receptor agonists have shown activity in pre-clinical models of neuropathic pain states (7).
  • a method of treating psychosis comprising: identifying a subject suffering from one or more symptoms of psychosis; and contacting the subject with a therapeutically effective amount of N-desmethylclozapine; whereby the one or more symptoms of psychosis are ameliorated.
  • the subject is human.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the method further comprises contacting the subject with an additional therapeutic agent.
  • the subject is contacted with the additional therapeutic agent subsequent to the contacting with N-desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent prior to the contacting with N- desmethylclozapine. In still another embodiment, the subject is contacted with the additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine repuptake inhibitiors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reupake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotonin IA agonists, anti epileptic and peripherally acting muscarinic antagonists.
  • Also disclosed herein is a method of treating affective disorders comprising: identifying a subject suffering from one or more symptoms of an affective disorder; and administering a therapeutically effective amount of N-desmethylclozapine to the subject, whereby the one or more symptoms of the affective disorder are ameliorated.
  • the subject is human.
  • the affective disorder is depression.
  • the affective disorder is mania.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the method further comprises administering to the subject an additional .therapeutic agent.
  • the subject is contacted with the additional therapeutic agent subsequent to the contacting with N-desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent prior to the contacting with N-desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • Also disclosed herein is a method of treating dementia, comprising: identifying a subject suffering from one or more symptoms of dementia; and administering a therapeutically effective amount of N-desmethylclozapine to said subject, whereby a desired clinical effect is produced.
  • the subject is human.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the dementia manifests as a cognitive impairment.
  • the dementia manifests as a behavioral disturbance.
  • the method further comprises administering to the subject an additional therapeutic agent.
  • the subject is contacted with the additional therapeutic agent subsequent to the contacting with N-desmethylclozapine. In another embodiment, the subject is contacted with the additional therapeutic agent prior to the contacting with N-desmethylclozapine. In still another embodiment, the subject is contacted with the additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • a method of treating neuropathic pain comprising: identifying a subject suffering from one or more symptoms of neuropathic pain; and contacting said subject with a therapeutically effective amount of N- desmethylclozapine, whereby the symptoms of neuropathic pain are reduced.
  • the subject is human.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the method further comprises contacting the subject with an additional therapeutic agent.
  • the subject is contacted with the additional therapeutic agent subsequent to the contacting with N-desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent prior to the contacting with N-desmethylclozapine. In still another embodiment, the subject is contacted with the additional therapeutic agent substantially simultaneously with N- desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • a method of treating glaucoma comprising: identifying a subject suffering from one or more symptoms of glaucoma; and contacting said subject with a therapeutically effective amount of N-desmethylclozapine, whereby the symptoms of glaucoma are reduced.
  • the subject is human.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the symptoms of glaucoma are selected from the group consisting of elevated intraocular pressure, optic nerve damage, and decreased field of vision.
  • the method further comprises contacting the subject with an additional therapeutic agent.
  • the subject is contacted with the additional therapeutic agent subsequent to the contacting with N-desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent prior to the contacting with N- desmethylclozapine.
  • the subject is contacted with the additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptics, prostenoids and alpha and beta adrenergic agonists.
  • a pharmaceutical composition comprising a pharmaceutically effective amount of N-desmethylclozapine and an additional therapeutic agent.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • the additional therapeutic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium.
  • the additional therapeutic gent is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril®), haloperidol (Haldol®), pimozide (Orap®), clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), quetiapine (Seroquel®), risperidone (Risperidal®), ziprasidone (Geodon®), lithium carbonate, Aripiprazole (Abilify), Clozapine, Clozaril, Compazine,
  • the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, venlafaxine, and pharmaceutically acceptable salts and prodrugs thereof.
  • the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.
  • the dual serotonin and norepinephrine reuptake inhibitor is selected from the group consisting of duloxetine, milnacripran and fluvoxamine.
  • the dopamine agonist is selected from the group consisting of cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, L-DOPA and bromocriptine.
  • the inverse serotonin agonists selected from the group consisting of N-(l-methylpiperidin-4-yl)-N-(4- flourophenylmethyl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide, MDL 100,907, SR-43694B (eplivanserin), ritanserin, ketanserin, mianserin, cinanserin, mirtazepine, cyproheptadine and cinnarizine.
  • One embodiment of the present invention includes, a method of treating cognitive impairment comprising identifying a subject in need of improvement of cognition and administering an amount of N-desmethylclozapine to said subject, which is therapeutically effective in improving the cognition of said subject.
  • the subject is human.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a single dose. In other aspects of this embodiment, the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the method further comprises contacting the subject with an additional therapeutic agent.
  • the subject may be contacted with said additional therapeutic agent subsequent to said contacting with N- desmethylclozapine.
  • the subject may be contacted with said additional therapeutic agent prior to said contacting with N-desmethylclozapine.
  • the subject is contacted with said additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotonin IA agonists, anti epileptic and peripherally acting muscarinic antagonists.
  • the subject suffers from a condition selected from the group consisting of hallucinations, delusions, disordered thought, behavioral disturbance, aggression, suicidality, mania, anhedonia, flattening of affect, affective disorders, depression, mania, dementia, neuropathic pain, glaucoma and two or more any of the foregoing conditions.
  • Another embodiment of the present invention includes method of ameliorating at least one symptom of a condition where it is beneficial to increase the level of activity of an Ml muscarinic receptor comprising determining that a subject would benefit from an increased level of activity of an Ml muscarinic receptor and administering an amount of N-desmethylclozapine which is therapeutically effective to increase the level of activity of the Ml muscarinic receptor and to ameliorate said at least one symptom to the subject.
  • the therapeutically effective amount of N- desmethylclozapine is administered as a single dose.
  • the therapeutically effective amount of N-desmethylclozapine is administered as a plurality of doses.
  • the method further comprises contacting the subject with an additional therapeutic agent.
  • the subject may be contacted with said additional therapeutic agent subsequent to said contacting with N- desmethylclozapine.
  • the subject may be contacted with said additional therapeutic agent prior to said contacting with N-desmethylclozapine.
  • the subject is contacted with said additional therapeutic agent substantially simultaneously with N-desmethylclozapine.
  • the additional therapeutic agent is selected from the group consisting of monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reuptake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotoninlA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • the subject suffers from a condition selected from the group consisting of hallucinations, delusions, disordered thought, behavioral disturbance, aggression, suicidality, mania, anhedonia, flattening of affect, affective disorders, depression, mania, dementia, neuropathic pain, glaucoma and two or more any of the foregoing conditions.
  • Another aspect of the present invention is a method for ameliorating one or more symptoms of psychosis, comprising administering to a subject exhibiting one or more symptoms of psychosis a therapeutically effective amount of N-desmethylclozapine essentially free of clozapine.
  • One embodiment further comprises identifying a subject exhibiting one or more symptoms of psychosis.
  • the psychosis is induced by exposure of the subject to one or more medications.
  • the subject is human.
  • the N-desmethylclozapine is administered as a single daily dose or administered in divided doses.
  • the N- desmethylclozapine is administered two, three or four times daily.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of an affective disorder, comprising administering to a subject exhibiting one or more symptoms of an affective disorder a therapeutically effective amount of N-desmethylclozapine essentially free of clozapine.
  • One embodiment further comprises identifying a subject exhibiting one or more symptoms of an affective disorder.
  • the affective disorder is depression.
  • the affective disorder is mania.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of dementia, comprising administering to a subject exhibiting one or more symptoms of dementia a therapeutically effective amount of N-desmethylclozapine essentially free of clozapine.
  • One embodiment further comprises identifying a subject exhibiting one or more symptoms of dementia, hi one embodiment, the dementia comprises cognitive impairment. In one embodiment, the dementia comprises behavioral disturbances.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of neuropathic pain, comprising administering to a subject exhibiting one or more symptoms of neuropathic pain a therapeutically effective amount of N- desmethylclozapine essentially free of clozapine.
  • One embodiment further comprises identifying a subject exhibiting one or more symptoms of neuropathic pain.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of glaucoma, comprising administering to a subject exhibiting one or more symptoms of glaucoma a therapeutically effective amount of N-desmethylclozapine essentially free of clozapine.
  • One embodiment further comprises identifying a subject exhibiting one or more symptoms of glaucoma.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of psychosis, comprising administering to a subject N- desmethylclozapine in combination with another anti-psychotic agent, wherein at least a portion of the N-desmethylclozapine is administered by directly introducing N- desmethylclozapine to the subject.
  • directly introducing N- desmethylclozapine to the subject comprises orally administering N-desmethylclozapine.
  • directly introducing N-desmethylclozapine to the subject comprises intravenous injection of N-desmethylclozapine.
  • the other anti ⁇ psychotic agent is selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and a salt of lithium.
  • the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).
  • the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).
  • the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®).
  • the benzisoxidil is selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).
  • the salt of lithium is lithium carbonate.
  • the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify), Clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa, or pharmaceutically acceptable salts thereof.
  • Aripiprazole Abilify
  • Clozapine Clozaril
  • Compazine Etrafon
  • Geodon Haldol
  • Inapsine Loxitane
  • Mellaril Moban
  • Navane Olanzapine
  • Orap Permitil
  • Prolixin Phenergan
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of psychosis, including administering to a subject exhibiting one or more symptoms of psychosis a therapeutically effective amount of a pharmaceutical composition comprising N-desmethylclozapine and a pharmaceutically acceptable excipient or diluent, wherein the amount of any clozapine administered is low enough such that the combined N-desmethylclozapine and clozapine result in a net agonism at muscarinic receptors.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of an affective disorder, including administering to a subject exhibiting one or more symptoms of an affective disorder a therapeutically effective amount of a pharmaceutical composition comprising N-desmethylclozapine and a pharmaceutically acceptable excipient or diluent, wherein the amount of any clozapine administered is low enough such that the combined N-desmethylclozapine and clozapine result in a net agonism at muscarinic receptors.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of dementia, including administering to a subject exhibiting one or more symptoms of dementia a therapeutically effective amount of a pharmaceutical composition comprising N-desmethylclozapine and a pharmaceutically acceptable excipient or diluent, wherein the amount of any clozapine administered is low enough such that the combined N-desmethylclozapine and clozapine result in a net agonism at muscarinic receptors.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of neuropathic pain, including administering to a subject exhibiting one or more symptoms of neuropathic pain a therapeutically effective amount of a pharmaceutical composition comprising N-desmethylclozapine and a pharmaceutically acceptable excipient or diluent, wherein the amount of any clozapine administered is low enough such that the combined N-desmethylclozapine and clozapine result in a net agonism at muscarinic receptors.
  • Another aspect of the present invention is a method of ameliorating one or more symptoms of glaucoma, including administering to a subject exhibiting one or more symptoms of glaucoma a therapeutically effective amount of a pharmaceutical composition comprising N-desmethylclozapine and a pharmaceutically acceptable excipient or diluent, wherein the amount of any clozapine administered is low enough such that the combined N-desmethylclozapine and clozapine result in a net agonism at muscarinic receptors.
  • Figure 1 is a graph showing the results of agonist activity of N- desmethylclozapine at Ml muscarinic acetylcholine receptors in R-SAT Assays.
  • Figure 2 is a graph showing the results of agonist activity of N- desmethylclozapine at Ml musacrinic acetylcholine receptors in Phosphatidyl Inositol Assay.
  • Figure 3 shows photographs of MAP kinase activation in rat hippocampus following parenteral administration of N-desmethylclozapine.
  • Figure 4A shows a graph of the muscarinic Ml receptor agonist activity of a library of 462 compounds as determined by R-SAT assays. Ml receptor efficacy data shown are derived from the 1 -micromolar concentration of compound, and are reported as percentage efficacy relative to the maximal response observed for a saturating 40- micromolar concentration of carbachol (100%).
  • Figures 4B-D shows a graph of PI hydrolysis data utilizing Chinese Hamster Ovary cells stably transfected with the human Ml receptor gene. Panel B depicts agonist responses reported as the percentage response observed for carbachol.
  • Drugs depicted are carbachol (squares), clozapine (triangles), and N-desmethylclozapine (circles), with observed potencies (pEC 50 ) of: carbachol (5.7), N- desmethylclozapine (6.7), and clozapine (no response).
  • Panel C depicts competitive antagonist responses obtained in the presence of a 3-micromolar concentration of carbachol, and are reported as the percentage response observed for atropine (100%).
  • Drugs depicted are atropine (squares), clozapine (triangles), and N-desmethylclozapine (circles), with observed potencies (pKi) of: atropine (8.5), N-desmethylclozapine (no response), and clozapine (7.1).
  • Panel D depicts competitive antagonist responses obtained in the presence of a 0.15-micromolar concentration of N-desmethylclozapine, and are reported as the percentage response observed for atropine (100%). Drugs depicted are atropine (squares), and clozapine (triangles), with observed potencies (pKi) of: atropine (8.4), and clozapine (7.6).
  • Figure 5 shows Ml muscarinic receptor agonist activity of N- desmethylclozapine in mouse hippocampus.
  • Phospho-MAPK immunoreactivity in the cell bodies and proximal dendrites of CAl pyramidal cells is shown following the administration of vehicle (A), clozapine at 30 mg/kg (B), N- desmethylclozapine at 10 (C), 30 (D), 100 (E), or N-desmethylclozapine (30mg/kg) and scopolamine (0.3 mg/kg, i.p.)(F).
  • Figure 7 shows the results of an R-SAT assay with a combination of 150 nM NDMC and varying concentrations of clozapine.
  • Figure 8 shows the results of a PI hydrolysis assay with a combination of 150 nM NDMC and varying concentrations of clozapine.
  • N-desmethylclozapine, 8- chloro -11- (1-piperazinyl) -5H- dibenzo [b,e] [1,4] diazepine, also known as NDMC, is defined as the compound having the molecular structure depicted in Formula (I).
  • An "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • an "antagonist” is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of an agonist or inverse agonist on the receptor.
  • an antagonist also known as a “neutral” antagonist
  • a partial agonist is defined as an agonist that displays limited, or less than complete, activity such that it fails to activate a receptor in vitro, functioning as an antagonist in vivo.
  • subject refers to an animal, preferably a mammal, and most preferably a human, who is the object of treatment, observation or experiment.
  • terapéuticaally effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes alleviation of the symptoms of the disease being treated.
  • the method disclosed herein includes administering a therapeutically effective amount of NDMC to a subject for the purpose of treating psychosis.
  • the above method for treating psychosis comprises identifying a subject suffering from one or more symptoms of psychosis; and contacting the subject with a therapeutically effective amount of N-desmethylclozapine; whereby the one or more symptoms of psychosis are ameliorated.
  • the symptom is cognitive impairment associated with psychosis.
  • the subject suffering from psychosis exhibits more than one symptom of psychosis.
  • one of the symptoms is cognitive impairment while another symptoms is one or more of hallucinations, delusions, disordered thought, behavioral disturbance, aggression, suicidality, mania, anhedonia, or flattening of affect.
  • the method includes administering a therapeutically effective amount of NDMC to a subject for the purpose of treating depression or mania.
  • the method includes administering a therapeutically effective amount of NDMC to a subject for the purpose of treating the psychiatric and other behavioral disturbances characteristic of dementia or cognitive impairment of any origin.
  • the method includes administering a therapeutically effective amount of NDMC to a subject for the purpose of treating neuropathic pain.
  • the present inventors have profiled a large series of drugs that have utility in treating human disease for functional activity at the five human muscarinic receptor subtypes.
  • muscarinic drugs only two agents studied (out of more than 500) displayed muscarinic receptor agonist activity.
  • this compound has been shown to possess weak partial agonist/antagonist activity at muscarinic Ml, M2, and M4 receptors (9, 10), while in vivo it is generally considered to display muscarinic receptor antagonist properties.
  • the other was the related compound N-desmethylclozapine.
  • clozapine-N-oxide is a polar metabolite that is rapidly excreted and likely does not contribute to the biological activity of the parent compound.
  • NDMC N-desmethylclozapine
  • clozapine-N-oxide is a polar metabolite that is rapidly excreted and likely does not contribute to the biological activity of the parent compound.
  • NDMC constitutes 40-75% of the total serum clozapine concentrations during steady state kinetics in humans (13).
  • NDMC N-desmethylclozapine
  • a method of agonizing the activity of a muscarinic receptor comprising contacting the receptor with an effective amount of NDMC.
  • a method of treating a subject suffering from a muscarinic receptor related disorder comprising indentifying a subject in need thereof and administering to the subject a therapeutically effective amount of NDMC.
  • muscarinic related disorder it is meant a disorder whose symptoms are ameliorated by agonizing a muscarinic receptor.
  • a method of ameliorating one or more symptoms associated with schizophrenia or psychosis of any origin in a subject comprising administering to the subject a therapeutically effective amount of NDMC.
  • the method comprises contacting a subject with a pharmacologically active dose of NDMC, for the purpose of controlling the positive (hallucinations and delusion) and negative (apathy, social withdrawal, anhedonia) symptoms of schizophrenia or related psychosis, hi one embodiment, the NDMC administered to ameliorate one or more symptoms associated with schizophrenia or psychosis is essentially free of clozapine.
  • essentially free of clozapine it is meant that no appreciable amount of clozapine may be detected in the blood stream of the subject at the same time that NDMC is detectable in the blood stream of the subject, hi one embodiment, the amount of any clozapine administered with the NDMC is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors, hi one embodiment, some amount of clozapine is administered but it is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • the ratio of NDMC to clozapine is high enough to have a beneficial effect due to net agonism at muscarinic receptors. In various embodiments, the ratio of NDMC to clozapine is at least about 100:1, 50:1, 10: 1, 9: 1, 7:1, 5:1, or 3:1.
  • a method of ameliorating one or more symptoms associated with affective disorders comprising administering to the subject a therapeutically effective amount of NDMC.
  • the method comprises contacting a subject with a pharmacologically active dose of NDMC, for the purpose of controlling the symptoms observed during major depression or manic depression.
  • the NDMC administered to ameliorate one or more symptoms associated with affective disorders is essentially free of clozapine.
  • the amount of any clozapine administered with the NDMC is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors. In one embodiment, some amount of clozapine is administered but it is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • a method of ameliorating one or more symptoms associated with Alzheimer's Disease and related neurodegenerative disorders in a subject comprising administering to the subject a therapeutically effective amount of NDMC.
  • the method comprises contacting a subject with a pharmacologically active dose of NDMC, for the purpose of improving the cognitive deficits, and controlling the associated behavioral abnormalities, observed in degenerative dementias.
  • the NDMC administered to ameliorate one or more symptoms associated with dementia is essentially free of clozapine.
  • the amount of any clozapine administered with the NDMC is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • some amount of clozapine is administered but it is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • a method of ameliorate one or more symptoms associated with neuropathic pain in a subject comprising identifying a subject in need thereof and administering to the subject a therapeutically effective amount of NDMC.
  • the method comprises contacting a subject with a pharmacologically active dose of NDMC, for the purpose of controlling the dysthesthetic, hyperalgesic, and other altered nociceptive symptoms observed in neuropathic pain states regardless of their etiology.
  • the NDMC administered to ameliorate one or more symptoms associated with neuropathic pain is essentially free of clozapine.
  • the amount of any clozapine administered with the NDMC is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors. In one embodiment, some amount of clozapine is administered but it is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • a method of ameliorating one or more symptoms associated with glaucoma in a subject comprising administering to the subject a therapeutically effective amount of NDMC.
  • the method comprises contacting a subject with a pharmacologically active dose of NDMC, for the purpose of controlling the raised intra-ocular pressure observed in glaucoma, regardless of its etiology, hi one embodiment, the NDMC administered to ameliorate one or more symptoms associated with glaucoma is essentially free of clozapine.
  • the amount of any clozapine administered with the NDMC is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors. In one embodiment, some amount of clozapine is administered but it is low enough such that the combined NDMC and clozapine administered result in a net agonism at muscarinic receptors.
  • NDMC possesses potent agonist activity at the human muscarinic receptors. It is further disclosed herein that NDMC can cross the blood brain barrier, and function in vivo as a muscarinic receptor agonist measured via the activation of MAP kinase activity in rat hippocampus.
  • a method of activating an Ml muscarinic receptor comprising contacting the receptor with N-desmethylclozapine.
  • N-desmethylclozapine ⁇ DMC
  • ⁇ -desmethylclozapine has the structure of Formula (I).
  • ⁇ DMC is prepared as previously described (17).
  • the dibenzo-diazepine- lactam precursor (II) is converted to the thiolactam (III) using phosphorus pentasulf ⁇ de, followed by alkylation with e.g. dimethyl sulfate to give the imino thioether (IV).
  • Aminolysis of the thioether with an excess of piperazine gives the desired N- desmethylclozapine (I).
  • the dibenzo-diazepine-lactam (II) may be converted into the imino-chloride (V) by treatment with a halogenating agent such as phosphorus pentachloride and the product V is converted to N-desmethylclozapine (I) by reaction with piperazine.
  • a halogenating agent such as phosphorus pentachloride
  • NDMC may be formulated in pharmaceutical compositions comprising NDMC together with a pharmaceutically acceptable dilutant or excipient. Such compositions may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington 's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton PA, 1990. hi some embodiments, a pharmaceutical composition comprising NDMC is provided that is essentially free of clozapine.
  • NDMC may be administered in a single daily dose, or the total daily dosage may be administered as a plurality of doses, (e.g., divided doses two, three or four times daily).
  • compound for the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, or via topical use of ocular formulations, or using those forms of transdermal skin patches well known to persons skilled in the art.
  • the dosage regimen of NDMC can be selected in accordance with a variety of factors. These include type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder that is being treated.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1000 mg per adult human per day.
  • An effective amount of the drug is ordinarily supplied at a dosage level of about 0.0001 mg/kg to about 25 mg/kg body weight per day.
  • the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day.
  • the compounds may be administered on a regimen of 1 to 4 times per day.
  • NDMC may be used alone at appropriate dosages defined by routine testing in order to obtain optimal pharmacological effect, while minimizing any potential toxic or otherwise unwanted effects.
  • NDMC may be used as adjunctive therapy with known drugs to reduce the dosage required of these traditional drugs, and thereby reduce their side effects.
  • NDMC is administered in combination with one or more additional therapeutic agents.
  • the additional therapeutic agents can include, but are not limited to, a neuropsychiatric agent.
  • a neuropsychiatric agent refers to a compound, or a combination of compounds, that affects the neurons in the brain either directly or indirectly, or affects the signal transmitted to the neurons in the brain. Neuropsychiatric agents, therefore, may affect a person's psyche, such as the person's mood, perception, nociception, cognition, alertness, memory, etc.
  • the neuropsychiatric agent may be selected from the group consisting of monoamine reputkate inhibitiors, selective serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, dual serotonin and norepinephrine reupake inhibitors, dopamine agonists, antipsychotic agents, inverse serotonin agonists, serotonin antagonists, serotonin 2 inverse agonists, serotonin 2 antagonists, serotonin IA agonists, antiepileptic and peripherally acting muscarinic antagonists.
  • the antipsychotic agent may be selected from the group consisting of a phenothiazine, phenylbutylpiperadine, debenzapine, benzisoxidil, and salt of lithium.
  • the phenothiazine group of compounds may be selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).
  • the phenylbutylpiperadine group of compounds may be selected from the group consisting of haloperidol (Haldol®), and pimozide (Orap®).
  • the debenzapine group of compounds may be selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®) and quetiapine (Seroquel®).
  • the benzisoxidil group of compounds may be selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).
  • the salt of lithium may be lithium carbonate.
  • the antipsychotic agent may be selected from the group consisting of Aripiprazole (Abilify), Clozapine, Clozaril, Compazine, Etrafon, Geodon, Haldol, Inapsine, Loxitane, Mellaril, Moban, Navane, Olanzapine (Zyprexa), Orap, Permitil, Prolixin, Phenergan, Quetiapine (Seroquel), Reglan, Risperdal, Serentil, Seroquel, Stelazine, Taractan, Thorazine, Triavil, Trilafon, and Zyprexa, or pharmaceutically acceptable salts thereof.
  • Aripiprazole Abilify
  • Clozapine Clozaril
  • Compazine Etrafon
  • Geodon Haldol
  • Inapsine Loxitane
  • Mellaril Moban
  • Navane Olanzapine
  • Orap Permitil
  • Prolixin Phenergan
  • the selective serotonin reuptake inhibitor is selected from the group consisting of fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts or prodrugs thereof.
  • the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.
  • the dopamine agonist is selected from the group consisting of cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.
  • the inverse serotonin 2A agonist is N-(I- methylpiperidin-4-yl)-N-(4-flourophenylmethyl)-N'-(4-(2- methylpropyloxy)phenylmethyl)carbamide, MDL 100,907, SR-43694B (eplivanserin), rtianserin, ketanserin, mianserin, cinanserin, mirtazepine, cyproheptadine and cinnarizine.
  • the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) and a neuropsychiatric agent, hi yet another aspect, the present disclosure is directed to a method of treating neuropsychiatric disorder in a patient comprising identifying a patient in need thereof and administering to said patient a therapeutically effective amount of a compound of Formula (I) and a therapeutically effective amount of a neuropsychiatric agent.
  • NDMC and additional therapeutic agent(s) are administered nearly simultaneously.
  • these embodiments include those in which the compounds are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains the compounds.
  • the embodiments also include those in which each compound is in a separate administrable composition, but the patient is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.
  • one of NDMC and an additional therapeutic compound is administered first and then the other one of NDMC and the additional therapeutic compound is administered second.
  • the patient may be administered a composition comprising one of the compounds and then at some time, a few minutes or a few hours later, be administered another composition comprising the other one of the compounds.
  • Also included in these embodiments are those in which the patient is administered a composition comprising one of the compounds on a routine or continuous basis while receiving a composition comprising the other compound occasionally.
  • NDMC is administered in combination with another therapeutic agent, wherein at least a portion of the NDMC is administered by directly introducing NDMC to a subject.
  • clozapine may be administered in combination with NDMC wherein both clozapine and NDMC are directly administered to a subject.
  • a portion of the NDMC administered to the patient will be due to metabolism of clozapine.
  • another portion of NDMC will be due to direct administration of NDMC.
  • directly introducing NDMC to a subject may be accomplished by the subject orally ingesting NDMC.
  • directly introducing NDMC to a subject may be accomplished by intravenously injecting NDMC into the subject.
  • R-SAT Receptor Selection and Amplification Technology
  • Defining the functional pharmacological activity of NDMC at a given receptor can be achieved by a variety of methodologies. Another currently favored assay is the PI Hydrolysis assay (18).
  • R-SAT Receptor Selection and Amplification Technology
  • clozapine displays high potency (pECso °f " 7.2) yet limited intrinsic efficacy ( ⁇ 25% relative efficacy) at human Ml receptors.
  • Clozapine is thus defined as a weak partial agonist. Partial agonists lack sufficient intrinsic agonist activity to stimulate the receptor in a manner similar to full agonists. They thus behave as antagonists in vivo.
  • NDMC also displays high potency (PEC50 of 7.2) at human
  • Ml receptors yet it displays significantly greater intrinsic agonist activity at Ml receptors (65% relative efficacy to carbachol), behaving as a robust agonist in R-SAT assays. This increased efficacy suggests that NDMC will act as an agonist in vivo, a functional profile distinct from that observed for clozapine.
  • Clozapine and NDMC were tested at the remaining muscarinic receptor subtypes. These data are disclosed in Table 2.
  • the data in Table 2 are derived from R-SAT assays as previously described (20). Potency is reported as PEC50 values and efficacy is reported as that relative to the full agonist carbachol, both +/- standard deviation. N denotes number of experimental determinations. Table 2
  • NDMC displays increased intrinsic activity at all five muscarinic receptor subtypes when compared to clozapine.
  • the profile of NDMC at human muscarinic receptors is most similar to that observed for the investigational agent Xanomeline, with one important distinction, a significantly lower efficacy at human m3 receptors.
  • NDMC hippocampal MAP kinase
  • NDMC is an antagonist of D 2 dopamine receptors and a potent inverse agonist of 5HT 2A receptors.
  • GPCRs biogenic amine G-protein-coupled receptors
  • NDMC is a potent and efficacious muscarinic receptor agonist.
  • NDMC also displays agonism of M 2 , M 3 , and M 4 receptors, however this interaction is 10-fold less potent than the interaction with other subtypes and indeed, under physiological conditions NDMC is able to competitively antagonize M 3 receptors.
  • clozapine is a potent competitive antagonist of Mj, M 3 , and M 5 receptors, a weak agonist of M 2 receptors, and a potent partial agonist of M 4 receptors.
  • olanzapine an antipsychotic structurally related to NDMC and clozapine is an antagonist of all 5 muscarinic subtypes.
  • Haloperidol, risperidone, and ziprasidone do not interact with any of these receptors at concentrations up to 1 ⁇ M.
  • the agonist activity of NDMC at muscarinic receptors, particularly Mi and M 5 receptors, is unique among antipsychotic drugs.
  • NDMC In addition to its activity at D 2 , 5HT 2A , and muscarinic receptors, NDMC has affinity for ⁇ i, ⁇ 2 , Dj, Hi, ⁇ 2 , 5HTi A , 5HTIB, 5HT 3 , 5HT 6 , and 5HT 7 receptors, and Ca 2+ channels in ligand binding assays. Functionally it is a potent competitive antagonist of 5HT 2 c, Hi, and ⁇ iA receptors and an inverse agonist of 5HT 6A and 5HT 7 A receptors. [0089] NDMC is orally active in two models thought to be predictive of antipsychotic activity.
  • NDMC Like clozapine, NDMC attenuates both MK-801 -induced and amphetamine-induced hyperactivity in mice at doses lower or similar to those that reduce spontaneous activity. Unlike clozapine and haloperidol, NDMC does not attenuate apomorphine-induced climbing in mice. This may reflect the reduced affinity of NDMC for D 2 receptors compared to these other antipsychotics. NDMC administration results in a dose-dependent activation of mitogen-activated protein kinase (MAPK) in the CAl region of hippocampus and this activation can be blocked by the non-selective muscarinic antagonist scopolamine.
  • MAPK mitogen-activated protein kinase
  • NDMC neuropeptide
  • clozapine The pharmacokinetics of NDMC and clozapine were investigated in rats and dogs. In both species, a single dose of NDMC was administered orally (10 mg/kg) or intravenously (1 mg/kg) and blood samples were taken at regular intervals post-dose. The data showed that the oral bioavailability of NDMC is 25% and 44% in rats and dogs, respectively, hi comparison, the oral bioavailability of clozapine is 1.5% and 7% in rats and dogs, respectively. Thus these data indicate that NDMC has superior oral bioavailability relative to clozapine.
  • the brain-to-plasma ratio of NDMC was calculated in rats. The ratio was 1.0 at 240 minutes after oral administration of NDMC and 2.6 at 240 minutes after oral administration of clozapine. Together with data available in the literature, these results show that NDMC distributes into the CNS.
  • Example 4 In Vitro Pharmacology of NDMC
  • ' nr no significant antagonist or inverse agonist activity up to 1 ⁇ M.
  • NDMC neuropeptide /D 2 receptor potency ratio
  • Hi and ⁇ i A receptor antagonist an Hi and ⁇ i A receptor antagonist than clozapine, suggesting that it may have less of a propensity to induce adverse clinical effects, including sedation and orthostatic hypotension, mediated by these receptor subtypes.
  • NDMC was a potent, partial agonist of human Mi and M 5 receptors and a less potent, full agonist of human M 2 and M 4 receptors (Table 2); it lacked antagonist activity at these receptors under similar conditions (Table 1).
  • the physiological significance of M 2 and M 5 agonism in schizophrenia is unknown.
  • agonism of Mi and M 4 receptors is associated with antipsychotic activity (Bymaster FP, Felder C, Ahmned S and McKinzie D (2002). Muscarinic Receptors as a Target for Drugs Treating Schizophrenia. Curr Drug Targ CNS Neurol Dis, 1 : 163-181; Felder CC, Bymaster FP, Ward J and DeLapp N (2000).
  • NDMC Muscarinic Receptors as a Target for Drugs Treating Schizophrenia. Curr Drug Targ CNS Neurol Dis, 1: 163-181).
  • NDMC displays minimal, low potency agonist activity at M 3 receptors and behaves as an antagonist at this site (Tables 3 and 4).
  • Muscarinic M 3 receptors are the predominant receptor subtype that mediate cholinergic effects of parasympathetic activation in humans, such that significant agonist activity would likely result in treatment-limiting parasympathetic side effects including sweating, ocular, and gastrointestinal dysfunction.
  • the antagonist activity of NDMC at M 3 suggests that severe parasympathetomimetic effects will not be observed in clinical testing.
  • the pharmacological activity of NDMC at the muscarinic receptors has been observed by others (Sur et al. PNAS 2003).
  • nr no significant agonist activity up to 10 ⁇ M
  • NDMC was administered subcutaneously (s.c.) or orally (p.o.) to male, adult Non-Swiss Albino (NSA) mice at 1, 10, or 30 mg/kg.
  • s.c. subcutaneously
  • p.o. p.o.
  • NDMC significantly reduced spontaneous activity at 10 and 30 mg/kg.
  • the maximal reduction was achieved at 30 minutes post-administration and was maintained for the duration of the experiment, 120 minutes.
  • This effect of NDMC was similar to that seen with clozapine, which reduced spontaneous locomotion at 3 and 10 mg/kg s.c. and p.o.
  • NDMC non-competitive N-methyl-D-aspartate agonists
  • MK-801 non-competitive N-methyl-D-aspartate agonists
  • NDMC was evaluated for its ability to attenuate MK-801 -induced hyperactivity in male, adult, NSA mice and its activity in this assay was compared to that of clozapine.
  • NDMC attenuated MK-801 - induced hyperactivity with a minimal effective dose of 1 mg/kg s.c. and 10 mg/kg p.o., consistent with antipsychotic-like efficacy.
  • These doses were lower than or similar to those that reduced spontaneous locomotion, suggesting that the antipsychotic-like effects can be differentiated from general locomotor behavioral disruption.
  • clozapine reduced MK-801 -induced hyperactivity with a minimal effective dose of 1 mg/kg s.c. and 3 mg/kg p.o.
  • Example 7 Effect of NDMC on the Reversal of Amphetamine-induced Locomotor Behaviors in Non-Swiss Albino Mice
  • NDMC mitogen-activated protein kinase
  • NDMC resulted in the induction of cFOS expression in the pre-frontal cortex and nucleus accumbens, but not in striatum, and these effects were similar in magnitude and regional selectivity to those observed for clozapine.
  • the lack of cFOS expression in the striatum of NDMC-treated animals may indicate a low propensity for NDMC to cause EPS.
  • Example 11 Pharmacokinetic Evaluation of Clozapine and N-Desmethylclozapine following Administration of a Single Intravenous Dose or Oral Dose to Conscious Sprague Dawley Rats
  • NDMC N-desmethylclozapine
  • NDMC is a major chemical moiety formed after oral administration of clozapine in the rat.
  • NDMC is the primary clozapine metabolite formed by rat liver microsomes (Bun H, Disdier B, Aubert C and Catalin J (1999). Interspecies variability and drug interactions of clozapine metabolism by microsomes. Fund Clin Pharm, 13: 577-581).
  • the pharmacokinetic study described above included an initial assessment of the distribution of NDMC into brain.
  • the ratio of brain-to-plasma levels of NDMC was 0.36 ⁇ 0.16 at 60 minutes and 1.0 ⁇ 0.4 at 240 minutes following oral administration of 10 mg/kg NDMC to Sprague-Dawley rats. Additionally, after oral administration of clozapine the brain-to-plasma ratio of NDMC was 0.26 ⁇ 0.07 at 60 minutes and 2.6 ⁇ 0.8 at 240 minutes.
  • NDMC N-desmethylclozapine
  • NDMC was absorbed from the gastrointestinal tract following oral administration with a C m3x of 286.3 ng/mL achieved by 3.3 h. NDMC had low clearance from the circulation, a low volume of distribution, and was approximately 44% orally bioavailable. Clozapine had poorer oral bioavailability (7%). These data suggest that NDMC may have acceptable pharmacokinetic properties after oral administration in humans and may indeed have improved pharmacokinetic properties as compared to clozapine.
  • NDMC was readily detectable in plasma following both intravenous and oral administration of clozapine.
  • the mean NDMC/clozapine AUC ratio was 0.056 after i.v. administration of clozapine and 0.161 (i.e., 16%) after oral administration.
  • NIH/3T3 cells plated at 70-80% confluency were transfected with various receptor cDNA (10-lOOng receptor and 20ng ⁇ -Gal reporter/well of a 96 well plate) using the Polyfect Reagent (Qiagen Inc.) as described in the manufacture's protocol.
  • ligands were added in Dulbecco's modified Eagle's medium supplemented with penicillin (100 U/ml), streptomycin (100 ⁇ g/ml) and 2% Cyto-SF3. After four to six days, the media was aspirated off, the cells were lysed, O-Nitrophenyl- beta-D-Galactopyranoside (ONPG) was added and the resulting absorbance was measured spectrophotometrically. Concentration response curves were performed as eight-point concentration response experiments run in duplicate, where the maximal antipsychotic concentrations varied from 10-25 micromolar, and data were analyzed using Excel fit and Graph Pad Prism.
  • O-Nitrophenyl- beta-D-Galactopyranoside O-Nitrophenyl- beta-D-Galactopyranoside
  • Reported EC 50 values represent the concentration of a ligand that produces a half-maximal response from a receptor in the absence of other ligands, and IC 50 values represent the concentration of a ligand that inhibits half of the agonist-induced activity.
  • PI hydrolysis assays were performed on Chinese Hamster Ovary cells stably transfected with the human Ml muscarinic receptor cDNA as described in Spalding et al (2002), and the data are derived from six or eight-point concentration response experiments performed in duplicate.
  • MAP Kinase assays utilized C57BL6 mice treated subcutaneously with either vehicle, clozapine, or N-desmethylclozapine with or without scopolamine, sacrificed two hours later, and phospho-MAPK immunoreactivity was assayed as described in Berkeley et al (2001). Briefly, after treatments which were administered s.c. at 60 min., mice were perfused with 100 ml of 4% paraformaldehyde followed with 100 ml of 10% sucrose. Brains were removed and cryoprotected in 30% sucrose overnight at 4 0 C. The next day, 50 ⁇ m slices were cut on a sliding microtome.
  • Slices were rinsed, treated with 3% H 2 O 2 for 10 minutes at room temperature and rinsed again. Slices were blocked in PBS containing 10 ⁇ g/ml avidin (Vector Laboratories Burlingame, CA), 0.1% triton-X and 4% normal goat serum (NGS) for 1 hour. Slices were rinsed and incubated in PBS containing 50 ⁇ g/ml biotin (Vector Laboratories Burlingame, CA), 2% NGS, and phospho-ERKl/2 antibody (Cell signal Technologies, Beverly, MA) at a concentration of 1 :250 and allowed to incubate overnight at 4 0 C.
  • PBS 10 ⁇ g/ml avidin
  • NGS normal goat serum
  • slices were rinsed and placed in PBS containing 2% NGS and biotinylated goat anti-rabbit (Vector Laboratories Burlingame, CA) at a concentration of 1:100 for 1 hour at 4 0 C.
  • Slices were rinsed and placed in horseradish peroxidase-conjugated avidin-biotin complex (Vector Laboratories Burlingame, CA) for 1 hour at 4 0 C.
  • Slices were rinsed and incubated in TSA Fluorescein tyramide for 10 min at room temperature.
  • Slices were treated with 10 mM CuSO 4 for 30 minutes, mounted onto glass slides with Vectashield mounting media (Vector Laboratories Burlingame, CA). Slides were visualized via a fluorescence microscope and digital images were analyzed with Scion image analysis software (Scion Corp. Frederick, MD).
  • Stepwise multiple-regression analysis including the dependent measure, dose, age, and gender was utilized to assess the contribution of NDMC to treatment response in schizophrenic subjects (Hasegawa et al 1993 and Lee et al 1999). The analysis was adjusted for baseline level of symptom severity, age, and dose, since dose was not fixed. The plasma samples chosen for the analyses were obtained at 6 weeks and 6 months after initiation of therapy, were related to the clinical measures obtained at those times, and were drawn 12 hours after the last clozapine dose. Only subjects who had received at least 100 mg of clozapine per day were included in the analysis, and some data were unavailable for these subjects at some time points.
  • Antipsychotics Amoxapine, Amisulpiride, Amperozide, Bromperidol, Butaclamol, Chlorproethazine, Chlorpromazine, Chlorprothixene, Cis-flupentixol, Clothiapine, Clozapine, Droperidol, Fananserin, Fluphenazine, Fluspiriline, Haloperidol, Loxapine, Mazapertine, M 100907, Melperone, Mesoridazine, Molindone, N-Desmethyl Clozapine, N-desmethylolanzapine, Ocaperidone, Octoclothepin, Olanzapine, Perazine, Perlapine, Pimozide, Pimpamperone, Promazine, Prothypendyl, Quetiapine, Remoxipride, Risperidone, Sertindole, Spiperone, Sulpride, Sultopride, Telfluda
  • Antidepressants/ Anxiolytics Acetyltryptophan, Acetyltryptophanamide, Alaprocate, Alprazolam, Amitriptyline, Barbital, Bromazepam, Buproprion, Buspirone, Chloral Hydrate, Clobazam, Clonazepam, Clomipramine, Clorgyline, Chlordiazepoxide, Chlormezanone, Continine, Compazine, Desipramine, Deprenyl, Desmethyldiazepam, Diazoxide, Doxepin, Flumazenil, Flunitrazepam, Fluoxetine, Flurazepam, Fluvoxamine, Imipramine, Indatraline, Iproniazid, Maprotiline, Meprobamate, Milnacipram, Minaprine, Mirtazepine, Modafinil, Nitrazepam, Nomifensine, Nortriptyline, Oxazep
  • CNS Miscellaneous 3PPP, 5-Aminopentanoic Acid, 5-Hydroxy MDA, 5-Methoxy DMT, 5-Methoxytryptamine, Acetaminophen, Acetylsalicylic Acid, Alprenelol, Amantadine, Amiodarone, AMPA, Apocodeine, Apomorphine, Atropine, Baclofen, Balperidone, Benztropine, Bicuculline, Bradykinin, Bretylium, BRL 37344, Bromocriptine, Cannabidiol, Carbemazepine, Carbidopa, Cyproheptadine, Cirazoline, D-Amphetamine, (D-Ser2)-Leu Enkephalin-Thr, (Leu 5) Enkephalin, D-Phenylalanine, Dibucaine, Diclofenac, Dihydroergotamine, DOI, Domperidone, Ebalzotan, E
  • Monoaminergic 7-OH-DPAT, 8-0H-DPAT, Alpha Methyl Serotonin, Arecoline, Astemizole, Bethanacol, Carbachol, CGS 12066A, Cinanserin, Chlo ⁇ heniramine, Cimetidine, Clobenpropit, CPP, Dihydroergocristine, Dimaprit, Diphenhydramine, Doxylamine, Eltoprazine, Famotidine, Histamine, Imetit, Isomaltane, Ketanserin, Loperamide, L-Tryptophan, LY 53857, mCPP, Mesulergine, Metergoline, Methergine, Methiothepin, Methysergide, Mexamine, Mianserin, MK 212, Mepyramine, Pheniramine, Phenylbiguanide, Pimethixene, Piperazine, Pirenpirone, Prazosin, Promethazine, Pyrilamine, Quiapazine,
  • Cardiovascular Acetazolamide, Adenosine, Albuterol, Atenolol, Amiloride, Amrinone, Bepridil, Caffeine, Catopril, CGS-15943, CGS-21680, CGP- 12177A, Chlorothiazide, Clonidine, Debrisoquin, Digitoxin, Digoxin, Diltiazem, Dipyridamole, Disopyramide, Dobutamine, Doxazosin, DPCPX, Epinephrine, Enalapril, Flunarizine, Furosemide, Guanabenz, Guanethidine, Hydralazine, Hydrochlorothiazide, Isoproterenol, Isosorbide, Lidocaine, Linisopril, Metaproterenol, Methoxamine, Metrifudil, Metolazone, Metoprolol, Midodrine, Minoxidil, N-Acethyl
  • a library of 462 clinically relevant drugs were profiled for functional activity at 33 of the 36 known human monoaminergic G-protein coupled receptors using the mammalian cell-based functional assay Receptor Selection and Amplification Technology (R-SAT).
  • Table 13 illustrates data on representative antipsychotic agents for receptors at which the most potent activities were observed. Potency data for five representative antipsychotics and the clozapine metabolite N-desmethylclozapine (NDMC) at 13 human monoamine receptor subtypes are shown. Potency data are reported as pKi values for the competitive antagonist studies, while inverse agonist data are reported as pEC 50 values, both derived from three to eight separate determinations +/- ' standard error.
  • Asterixes indicate the presence of agonist activity where the muscarinic receptor agonist potencies are reported in Table 14.
  • Ziprasidone displays limited but detectable agonist efficacy at human 5-HTi A receptors ( ⁇ 30% relative to 8-OH-DPAT), and a Ki > 1-micromolar when assayed as a competitive antagonist.
  • Clozapine, olanzapine, and a number of typical agents were found to possess potent muscarinic receptor antagonist properties. Importantly, no single antagonist activity differentiated clozapine from all other agents.
  • Figure 4A reports the results of the functional agonist screen of this compound library at the human Ml muscarinic acetylcholine receptor. Only four compounds, the known muscarinic receptor agonists arecoline and carbachol, moperone and N-desmethylclozapine (NDMC), the major metabolite of clozapine (Gauch and Michaelis 1971), were identified. Moperone displayed only a very low potency (EC 5 o>l-micromolar) interaction. In contrast, NDMC displayed an EC 50 of 100 nM with 80% efficacy (relative to carbachol) in this study.
  • NDMC N-desmethylclozapine
  • Muscarinic receptor (M1-M5) agonist activity of clozapine, N-desmethylclozapine, olanzapine, N-desmethylolanzapine, xanomeline, and carbachol was determined using R- SAT as previously described (Spalding et al 2002). Average efficacy (percentage relative to carbachol) and potency (pEC 50 ) +/- standard error are reported for 3 or more replicate determinations. No response denotes the lack of agonist activity at concentrations up to 10- micromolar.
  • Clozapine was found to be a very weak partial agonist at Ml receptors, a more efficacious agonist at M2 and M4 receptors, and to lack agonist activity at M3 and M5 receptors.
  • NDMC also displayed high potency interactions with all five human muscarinic receptors, but with increased agonist efficacy at Ml, M4, and M5 receptors when compared to clozapine (Table 14).
  • olanzapine and N- desmethylolanzapine both structurally related to clozapine and NDMC, lacked agonist activity at human muscarinic receptors.
  • xanomeline displayed a muscarinic receptor profile that is similar to that observed for NDMC, with the notable exception of higher agonist efficacy at M3 receptors.
  • the agonist activities of clozapine, NDMC, and xanomeline at human muscarinic receptor subtypes are unique among all neuropsychiatric agents tested ( Figure 4, and Tables 13 and 14).
  • the present inventors discovered that muscarinic receptor agonism, and Ml receptor agonism in particular, of NDMC can be achieved in vivo during pharmacotherapy with clozapine.
  • Clozapine and NDMC were tested for their ability to increase the phosphorylation of mitogen-activated protein kinase (MAP kinase) in the CAl region of mouse hippocampus, a response that has been shown to reflect Ml receptor activation (Berkeley et al 2001).
  • MAP kinase mitogen-activated protein kinase
  • Figure 5A subcutaneous administration of vehicle ( Figure 5A), clozapine ( Figure 5B), or scopolamine alone (data not shown) fails to stimulate phosphorylation of hippocampal MAP kinase.
  • clozapine has significant agonist activity at M2 and M4 receptors, and low agonist efficacy at Ml receptors (Zorn et al 1994 and Olianas et al 1999), consistent with the results reported herein.
  • clozapine has two major metabolites, NDMC and clozapine-N-oxide (Gauch and Michaelis 1971). After steady state dosing, NDMC represents a large proportion of total detectable moieties, with concentrations ranging from 20-150% of that observed for clozapine, with mean values of 60-80% (Bondesson and Lindstrom 1988 and Perry et al 1991).
  • NDMC is an active metabolite
  • Di, D 2 , and 5-HT 2 c receptor competitive antagonist activity Korean et al 1993
  • Ml receptor agonist activity Korean et al 2003
  • clozapine-N-oxide displays only very low potency (pKI's ⁇ 6.0) functional activity at human monoaminergic receptors (data not shown).
  • clozapine acting through its predominant metabolite NDMC, functions as a direct acting muscarinic receptor agonist in vivo.
  • the agonist actions of NDMC is attenuated by the antagonistic actions of the parent compound.
  • high NDMC levels, and particularly high NDMC/clozapine ratios increases agonist efficacy at muscarinic receptors, as predicted by mass action and by agonist/antagonist mixing studies (Brauner- Osborne et al 1996). Clinical data support this notion.
  • clozapine therapy usually lack the traditional anti-cholinergic side effects of dry mouth, blurred vision, and urinary retention common to classical muscarinic antagonists, it is unique in its ability to frequently produce sialorrhea (Baldessarini and Frankenburg 1991), an effect that can be blocked by the muscarinic antagonist pirenzepine (Fritze and Elliger 1995).
  • the muscarinic receptor agonist activity of NDMC likely mediates this peripheral effect, while the muscarinic receptor subtype responsible is still unknown, receptor subtypes in addition to the M3 have been implicated (Bymaster et al 2003).
  • NDMC/clozapine ratios are a better predictor of therapeutic response to clozapine, particularly for cognition, than absolute clozapine levels.
  • Table 15 Serum N-desmethylclozapine levels and clinical response in schizophrenia.
  • Table 15A reports the clozapine dose, clozapine level, NDMC levels, and NDMC/clozapine ratios for all treatment resistant (TR) subjects, responders, non-responders, and all subjects at 6 weeks and 6 months.
  • TR treatment resistant
  • P* reports statistically significant differences between responders and non-responders.
  • Table 15B reports the major relationships of interest for the prediction of the contribution of NDMC to response to clozapine treatment, including quality of life, negative symptoms, and cognition,
  • R refers to the model applied.
  • Abbreviations used include: NS-not significant, BPRS-Brief Psychiatric Rating Scale, SANS-Scale for the Assessment of Negative Symptoms, SAPS- Scale for the Assessment of Positive Symptoms, WISC-Wisconsin Card Sorting Test.
  • Stepwise multiple-regression were utilized to determine the best predictors of outcome from each of these measures, including baseline levels of the dependent measure, dose, age, and gender, since all have been shown to significantly predict response to clozapine (Table 15B).
  • muscarinic receptor agonist properties of NDMC also contribute to the efficacy of clozapine therapy against positive symptoms. Not only did high NDMC/clozapine ratios predict response to delusions as noted above, but additional support comes from the observation that there are several similarities between the central effects of muscarinic receptor agonists and dopamine D 2 receptor antagonists (Pfeiffer and Jenney 1957 and Mirza et al 2003). For example, behavioral pharmacological experiments with mice harboring targeted deletions of each of the five muscarinic receptor subtypes have shown that the Ml receptors plays a central role in DA-mediated behaviors (Gerber et al 2001).
  • xanomeline which displays some selectivity for Ml and M4 receptors inhibits amphetamine-induced locomotion (Shannon et al 2000). Clinically, xanomeline was found to diminish hallucinosis and aggression in Alzheimer's Disease patients (Bodick et al 1997), and has been shown to display activity against both positive and negative symptoms in a recent, small, Phase 2 study in schizophrenia (Schekhar et al, unpublished data). [0136] The central dopaminergic and muscarinic cholinergic systems are well known to be functionally interrelated (Miller and Hiley 1974).
  • clozapine The muscarinic antagonist properties of clozapine are thought to contribute to its low propensity to cause EPS, yet the anti-EPS effects of clozapine are more robust than those obtained by the adjunctive use of anticholinergics agents like trihexyphenidyl, and some EPS producing antipsychotics, e.g. thioridazine, also possess potent muscarinic receptor antagonist properties.
  • NDMC neurodegenerative neurodegenerative disease 2019
  • This activity was found to be unique among neuropsychiatric agents as a class. It is demonstrated that NDMC can cross the blood brain barrier and function as an Ml receptor agonist in vivo. Consideration of the contribution of NDMC to improvement in cognition and quality of life in clozapine treated patients shows that NDMC mediates clinically relevant aspects of treatment response that differentiate clozapine from other agents used to treat schizophrenia.
  • FIG. 8 depicts the results of the assay as a function of clozapine concentration.
  • the dotted line in Figure 8 indicates the maximum concentration of clozapine for which a net agonistic effect is observed.
  • net agonistic activity was observed for clozapine concentrations of about 100 nM and below, thus confirming that a ratio of NDMC to clozapine of about 1.5 and greater provide a net agonistic effect.
  • Example 15 Administration of Single Doses of NDMC to Schizophrenic Patients
  • a single-center, in-patient, randomized, double blind, placebo controlled, single dose study is conducted on two sequential group of patients. Two different groups of 6 patients each are enrolled. Each patient in the first group of patients receives single doses of placebo, 25 mg of NDMC, and 50 mg of NDMC sequentially in random order. Each patient in the second group of patients receives single doses of placebo, 75 mg of NDMC, and 100 mg of NDMC sequentially in random order.
  • the NDMC and placebo is administered orally as a powder in a gelatin capsule.
  • Male or female patients, 20 to 50 years of age, with a history of schizophrenia or schizoaffective disorder, who are otherwise in good health are selected for the study. The patients are not experiencing acute exacerbation of severe psychosis, defined as a Positive and Negative Syndrome Scale (PANSS) score greater than 75.
  • PANSS Positive and Negative Syndrome Scale
  • Plasma samples are analyzed for concentrations of NDMC.
  • Pharmacokinetic parameters are calculated including C max (maximum plasma concentration), t max (time to maximum plasma concentration), AUC O-Z (area under the plasma concentration time curve from time zero to the last quantifiable timepoint, calculated by linear-log trapezoidal summation), AUC 0- ⁇ (area under the plasma concentration time curve from time zero to infinity, calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant ⁇ z), ⁇ z (elimination rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve), t ⁇ n (terminal half-life, determined as ln(2)/ ⁇ z), and CL po (apparent oral clearance, calculated by Dose / AUC(O- ⁇ )).
  • Tolerability of NDMS is determined by measuring extrapyramidal (EPS) motor effect using the Simpson and Angus Sacle (SAS) and the Barnes Akathisia Scale (BAS). These scales are administered at baseline (Study Day -1), 3-5 hours after drug administration on Study Days 1 , 4, and 8, and at the End of Study evaluation.
  • SAS Simpson and Angus Sacle
  • BAS Barnes Akathisia Scale
  • Antipsychotic efficacy is measured using the PANSS and the Clinical Global Impression Scale-Schisophrenia (CGI-S) measures. These scales are administred at baseline (Study Day -1), on Study Days 1, 4, and 8, and at the End of Study evaluation.
  • CGI-S Clinical Global Impression Scale-Schisophrenia
  • Safety is evaluated by measuring vital signs including 3-positional blood pressure and pulse rate (5 minute supine, 1 minute sitting, 3 minutes standing), respiratory rate, and oral temperature except during screening and post-study procedures.
  • 12-lead ECGs are recorded and standard electrocardiogram parameters including QRS, PR, QT, and QTc intervals are measured.
  • continuous lead-II ECG monitoring is performed for the first 8 hours of Day 1, 4, and 8 following each NDMC or placebo dose administration.
  • a neurological screen is conducted by the clinically responsible physician at the clinic.
  • the neurological screen consists of a qualitative assessment of muscle tone in the extremities, the presence of tremors, fasiculations, and nystagmus, and various tests of cerebellar coordination (finger nose test, dysdiadochokinesia, heel-shin test, and gait).
  • Clinical laboratories are measured after at least an 8-hour fast on Study Days 1, 4, 8, and the End of Study evaluation and include the following:
  • Erythrocytes RBC count, hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), RDW, and reticulocyte count.
  • Leukocytes WBC count and differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) reported as absolute values.
  • Coagulation platelet count, PT as INR, and aPTT.
  • Liver alkaline phosphatase, ALT (serum glutamic-pyruvic transaminase [SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total, direct, indirect), gamma-glutamyl transferase (GGTP), creatine phosphokinase (CPK) and LDH.
  • ALT serum glutamic-pyruvic transaminase
  • AST seerum glutamic-oxaloacetic transaminase [SGOT]
  • bilirubin total, direct, indirect
  • GGTP gamma-glutamyl transferase
  • CPK creatine phosphokinase
  • Renal blood urea nitrogen (BUN), creatinine, and uric acid.
  • Electrolytes carbon dioxide, chloride, magnesium, potassium, and sodium.
  • General albumin, calcium, glucose (fasting) phosphate, and protein (total).
  • Endocrine prolactin
  • Lipids cholesterol (total), HDL cholesterol, LDL cholesterol, and triglycerides.
  • Macroscopic urinalysis pH, specific gravity, glucose, ketones, leukocyte esterase, nitrites, occult blood, and protein.
  • mice [0160] Microscopic urinalysis: RBC/high powered field, WBC/high powered field, bacteria, castes, epithelial cells, mucous threads and crystals.
  • Example 16 Administration of Multiple Doses of NDMC to Schizophrenic Patients
  • a single-center, in-patient, randomized, double blind, placebo controlled, multiple dose study is conducted on two sequential groups. Twelve patients, in two different groups of six patients each are enrolled. Each patient receives either placebo or NDMC daily for five days. The NDMC and placebo is administered orally as a powder in a gelatin capsule. Male or female patients, 20 to 50 years of age, with a history of schizophrenia or schizoaffective disorder, who are otherwise in good health are selected for the study. The patients are not experiencing acute exacerbation of severe psychosis, defined as a Positive and Negative Syndrome Scale (PANSS) score greater than 75.
  • PANSS Positive and Negative Syndrome Scale
  • a final End of Study evaluation is conducted 5-7 days after the cessation of active dosing on Study Day 5.
  • a safety assessment is performed during this clinical evaluation, including vital signs, ECG, clinical labs, NDMC serum determination, and adverse event recording. All patients are followed clinically, as in-patients, for as long as is indicated following the cessation of active dosing of NDMC.
  • Plasma samples are analyzed for concentrations of NDMC.
  • Pharmacokinetic parameters are calculated are calculated following the single dose administration on Day 1 including C max (maximum plasma concentration), t max (time to maximum plasma concentration), AUC 0-2 (area under the plasma concentration time curve from time zero to the last quantifiable timepoint, calculated by linear-log trapezoidal summation), AUCo - ⁇ (area under the plasma concentration time curve from time zero to infinity, calculated by linear-log trapezoidal summation and extrapolated to infinity by addition of the last quantifiable plasma concentration divided by the elimination rate constant ⁇ z), ⁇ (elimination rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve), ti /2 (terminal half-life, determined as ln(2)/ ⁇ z), and CL po (apparent oral clearance, calculated by Dose / AUC(O- ⁇ )).
  • Pharmacokinetic parameters are also calculated following the last dose on Day 5 including Cm aX ,ss (maximum steady-state plasma concentration), C m i n , ss (minimum steady-state plasma concentration), C avg)ss (average steady-state plasma concentration calculated as AUC(0- ⁇ ) ss divided by the dosing interval ⁇ ), t ma ⁇ , ss (time to maximum steady- state plasma concentration), t mm , ss (time to minimum steady-state plasma concentration), AUCo- z (area under the plasma concentration time curve from time zero to the last quantifiable timepoint, calculated by linear-log trapezoidal summation), AUC 0 .
  • ⁇ ss area under the plasma concentration time curve from time zero to the end of the steady-state dosing interval, calculated by linear-log trapezoidal summation
  • ⁇ z steady-state elimination rate constant, determined by linear regression of the terminal points of the log- linear plasma concentration-time curve
  • ti /2>ss steady-state terminal half-life, determined as ln(2)/ ⁇ z jSS
  • CL pOiSS apparent oral clearance, calculated by Dose / AUC(0- ⁇ ) ss ).
  • Tolerability of NDMS is determined by measuring extrapyramidal (EPS) motor effect using the Simpson and Angus Sacle (SAS) and the Barnes Akathisia Scale (BAS). These scales are administered at baseline (Study Day -1), 6 hours after drug administration on Study Days 1-5, and at the End of Study evaluation.
  • EPS extrapyramidal
  • SAS Simpson and Angus Sacle
  • BAS Barnes Akathisia Scale
  • Antipsychotic efficacy is measured using the PANSS and the Clinical Global Impression Scale-Schisophrenia (CGI-S) measures. These scales are administred at baseline (Study Day -1), on Study Days 1, 5, and at the End of Study evaluation.
  • CGI-S Clinical Global Impression Scale-Schisophrenia
  • Safety is evaluated by measuring vital signs including 3-positional blood pressure and pulse rate (5 minute supine, 1 minute sitting, 3 minutes standing), respiratory rate, and oral temperature except during screening and post-study procedures.
  • 12-lead ECGs are recorded and standard electrocardiogram parameters including QRS, PR, QT, and QTc intervals are measured.
  • continuous lead-II ECG monitoring is performed for the first 8 hours of Days 1-5 following each NDMC or placebo dose administration.
  • a neurological screen is conducted by the clinically responsible physician at the clinic.
  • the neurological screen consists of a qualitative assessment of muscle tone in the extremities, the presence of tremors, fasiculations, and nystagmus, and various tests of cerebellar coordination (finger nose test, dysdiadochokinesia, heel-shin test, and gait).
  • Clinical laboratories are measured after at least an 8-hour fast and include the following:
  • Erythrocytes RBC count, hematocrit, hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), RDW, and reticulocyte count.
  • Leukocytes WBC count and differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils) reported as absolute values.
  • Coagulation platelet count, PT as INR, and aPTT.
  • Liver alkaline phosphatase, ALT (serum glutamic-pyruvic transaminase [SGPT]), AST (serum glutamic-oxaloacetic transaminase [SGOT]), bilirubin (total, direct, indirect), gamma-glutamyl transferase (GGTP), creatine phosphokinase (CPK) and LDH.
  • ALT serum glutamic-pyruvic transaminase
  • AST seerum glutamic-oxaloacetic transaminase [SGOT]
  • bilirubin total, direct, indirect
  • GGTP gamma-glutamyl transferase
  • CPK creatine phosphokinase
  • Renal blood urea nitrogen (BUN), creatinine, and uric acid.
  • Electrolytes carbon dioxide, chloride, magnesium, potassium, and sodium.
  • Endocrine prolactin
  • Lipids cholesterol (total), HDL cholesterol, LDL cholesterol, and triglycerides.
  • Macroscopic urinalysis pH, specific gravity, glucose, ketones, leukocyte esterase, nitrites, occult blood, and protein.
  • Centorrino F., Baldessarini, R., J., Kando, J., C, et. al. (1994)
  • Clozapine and metabolites concentrations in serum and clinical findings during treatment of chronically psychotic patients. J. CHn. Psychopharmacol. 14: 119-125. [0198] Hunziker F. Fisher, E., and Scmutz, J. (1967) l l-amino-5H- dibenzo[b,e]-l,4-diazepine. Mitander ubertechnischglienrige Heterocyclen. HeIv. Chim. Acta, 50:1588-1599.
  • Clozapine is a potent and selective muscarinic antagonist at the five cloned human muscarinic acetylcholine receptors expressed in CHO-Kl cells. Eur J Pharmacol 192:205-206.
  • Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 269:R1-R2.

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