Selective serotonin receptor inverse agonists as therapeutics for disease

Abstract

Disclosed herein are pharmaceutical compositions comprising an inverse serotonin receptor agonist or a serotonin receptor antagonist and an anti-psychotic agent. Disclosed herein are also methods of treating psychotic disorders using the disclosed pharmaceutical compositions.

1 . A pharmaceutical composition comprising: 
 a first compound selected from the group consisting of an inverse agonist of a serotonin receptor, an antagonist of a serotonin receptor, and pharmaceutically acceptable salts thereof; and    a second compound selected from the group consisting of a SSRI, a SNRI, a MAO-I, a TCA, an antipsychotic agent, a norepinephrine reuptake inhibitor, a dopamine agonist, an anti-insomnia drug, an anti-manic drug, an anti-phobia drug, the compound of Formula (II)                          and pharmaceutically acceptable salts thereof.    
     
     
         2 . The pharmaceutical composition of  claim 1  wherein the serotonin receptor is a 5HT2A receptor.  
     
     
         3 . The pharmaceutical composition of  claim 2  wherein the first compound is a compound of Formula (I):  
       
         
           
           
               
               
           
         
       
     
     
         4 . The pharmaceutical composition of  claim 2  wherein the first compound is a compound of Formula (II):  
       
         
           
           
               
               
           
         
         and the second compound selected from the group consisting of a SSRI, a SNRI, a MAO-I, a TCA, an antipsychotic agent, a norepinephrine reuptake inhibitor, a dopamine agonist, an anti-insomnia drug, an anti-manic drug, and an anti-phobia drug.  
       
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the SSRI is selected from the group consisting of bupropion (Wellbutrin, Zyban), citalopram (Celexa), duloxetine, escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertaline (Zoloft), sibutramine, trazodone (Dividose), and venlafaxine.  
     
     
         6 . The pharmaceutical composition of  claim 1  wherein the SNRI is selected from the group consisting of citalopram (Celexa), dulexetine, escitalopram (Lexapro), fluvoxamine (Luvox), and venfalaxine (effexor).  
     
     
         7 . The pharmaceutical composition of  claim 1  wherein the MAO-I is selected from the group consisting of tranylcypromine (Parnate), phenelzine (Nardil), maprotiline, and isocarboxazid (Marplan).  
     
     
         8 . The pharmaceutical composition of  claim 1  wherein the TCA is selected from the group consisting of amitryptiline (Norpramine), amoxapineclomipramine (Anafranil), desipramine, doxepin (Sinequan), imipramine (Tofranil), maprotiline, (Elavil), protryptiline, and trimipramine.  
     
     
         9 . The pharmaceutical composition of  claim 1  wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperadine, a debenzapine, a benzisoxidil, and a salt of lithium.  
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).  
     
     
         11 . The pharmaceutical composition of  claim 9  wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).  
     
     
         12 . The pharmaceutical composition of  claim 9  wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).  
     
     
         13 . The pharmaceutical composition of  claim 9  wherein the benzisoxidil is selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).  
     
     
         14 . The pharmaceutical composition of  claim 9  wherein the salt of lithium is lithium carbonate.  
     
     
         15 . The pharmaceutical composition of  claim 1  wherein the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify), Etrafon Haldol, Inapsine, Mellaril, Moban, Navane, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Stelazine, Taractan, Triavil, and Trilafon.  
     
     
         16 . The pharmaceutical composition of  claim 1  wherein the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.  
     
     
         17 . The pharmaceutical composition of  claim 1  wherein the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.  
     
     
         18 . The pharmaceutical composition of  claim 1  wherein the anti-insomnia drug is selected from the group consisting of alprazolam (Xanax), chlordiazepoxide (Librium, Limbitrol), clorazepate (Tranxene), estazolam (ProSom), flurazepam (Dalmane), hydroxyzine (Atarax), lorazepam (Ativan), pentobarbital (Nembutal), quazepam (Doral), secobarbital (Seconal), temazepam (Restoril), triazolam (Halcion), valium, zaleplon (Sonata), zolpidem (Ambien), and the benzodiazepine family of drugs.  
     
     
         19 . The pharmaceutical composition of  claim 1  wherein the anti-manic drug is selected from the group consisting of divalproex (Depakote), lithium carbonate (Eskalith), and lithium citrate.  
     
     
         20 . The pharmaceutical composition of  claim 1  wherein the anti-phobia drug is D-cycloserine.  
     
     
         21 . The pharmaceutical composition of  claim 1 , further comprising physiologically acceptable carrier, diluent, or excipient, or a combination thereof.  
     
     
         22 . The pharmaceutical composition of  claim 1  wherein the first compound is the compound of Formula (I):  
       
         
           
           
               
               
           
         
         and the second compound is fluoxetine.  
       
     
     
         23 . A method of treating a disorder in a patient, the disorder selected from the group consisting of depression, mania, social phobia, psychosis, and a neuropsychiatric disorder, the method comprising: 
 identifying a patient in need of said treatment, and    administering to said patient a therapeutically effective amount of a combination of a first compound and a second compound, the first compound selected from the group consisting of an inverse agonist of a serotonin receptor, an antagonist of a serotonin receptor, and pharmaceutically acceptable salts thereof, the second compound selected from the group consisting of a SSRI, a SNRI, a MAO-I, a TCA, an antipsychotic agent, a norepinephrine reuptake inhibitor, a dopamine agonist, an anti-insomnia drug, an anti-manic drug, an anti-phobia drug, the compound of Formula (II)                          and pharmaceutically acceptable salts thereof.    
     
     
         24 . The method of  claim 23  wherein the neuropsychiatric disorder is selected from the group consisting of schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders, Tourette's Syndrome, drug-induced psychoses, and psychoses secondary to neurodegenerative disorders.  
     
     
         25 . The method of  claim 24  wherein said affective disorders is selected from the group consisting of major depression, bipolar disorder, and depression with psychotic features.  
     
     
         26 . The method of  claim 24  wherein said neurodegenerative disorders are selected from the group consisting of Alzheimer's and Huntington's Disease  
     
     
         27 . The method of  claim 23  wherein the serotonin receptor is a 5HT2A receptor.  
     
     
         28 . The method of  claim 27  wherein the first compound is a compound of Formula (I):  
       
         
           
           
               
               
           
         
       
     
     
         29 . The method of  claim 27  wherein the first compound is a compound of Formula (II):  
       
         
           
           
               
               
           
         
       
     
     
         30 . The method of  claim 23  wherein the SSRI is selected from the group consisting of bupropion (Wellbutrin, Zyban), citalopram (Celexa), duloxetine, escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), nefazodone (Serzone), paroxetine (Paxil), sertaline (Zoloft), sibutramine, trazodone (Dividose), and venlafaxine.  
     
     
         31 . The pharmaceutical composition of  claim 1  wherein the SNRI is selected from the group consisting of citalopram (Celexa), dulexetine, escitalopram (Lexapro), fluvoxamine (Luvox), and venfalaxine (effexor).  
     
     
         32 . The method of  claim 23  wherein the MAO-I is selected from the group consisting of tranylcypromine (Parnate), phenelzine (Nardil), maprotiline, and isocarboxazid (Marplan).  
     
     
         33 . The method of  claim 23  wherein the TCA is selected from the group consisting of amitryptiline (Norpramine), amoxapineclomipramine (Anafranil), desipramine, doxepin (Sinequan), imipramine (Tofranil), maprotiline, (Elavil), protryptiline, and trimipramine.  
     
     
         34 . The method of  claim 23  wherein the antipsychotic agent is selected from the group consisting of a phenothiazine, a phenylbutylpiperadine, a debenzapine, a benzisoxidil, and a salt of lithium.  
     
     
         35 . The method of  claim 34  wherein the phenothiazine is selected from the group consisting of chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), and thioridazine (Mellaril®).  
     
     
         36 . The method of  claim 34  wherein the phenylbutylpiperadine is selected from the group consisting of haloperidol (Haldol®) and pimozide (Orap®).  
     
     
         37 . The The method of  claim 34  wherein the debenzapine is selected from the group consisting of clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).  
     
     
         38 . The method of  claim 34  wherein the benzisoxidil is selected from the group consisting of resperidone (Resperidal®) and ziprasidone (Geodon®).  
     
     
         39 . The method of  claim 34  wherein the salt of lithium is lithium carbonate.  
     
     
         40 . The method of  claim 23  wherein the antipsychotic agent is selected from the group consisting of Aripiprazole (Abilify), Etrafon Haldol, Inapsine, Mellaril, Moban, Navane, Permitil, Prolixin, Phenergan, Reglan, Risperdal, Stelazine, Taractan, Triavil, and Trilafon.  
     
     
         41 . The method of  claim 23  wherein the norepinephrine reuptake inhibitor is selected from the group consisting of thionisoxetine and reboxetine.  
     
     
         42 . The method of  claim 23  wherein the dopamine agonist is selected from the group consisting of sumatriptan, almotriptan, naratriptan, frovatriptan, rizatriptan, zomitriptan, cabergoline, amantadine, lisuride, pergolide, ropinirole, pramipexole, and bromocriptine.  
     
     
         43 . The method of  claim 23  wherein the anti-insomnia drug is selected from the group consisting of alprazolam (Xanax), chlordiazepoxide (Librium, Limbitrol), clorazepate (Tranxene), estazolam (ProSom), flurazepam (Dalmane), hydroxyzine (Atarax), lorazepam (Ativan), pentobarbital (Nembutal), quazepam (Doral), secobarbital (Seconal), temazepam (Restoril), triazolam (Halcion), valium, zaleplon (Sonata), zolpidem (Ambien), and the benzodiazepine family of drugs.  
     
     
         44 . The method of  claim 23  wherein the anti-manic drug is selected from the group consisting of divalproex (Depakote), lithium carbonate (Eskalith), and lithium citrate.  
     
     
         45 . The method of  claim 23  wherein the anti-phobia drug is D-cycloserine.  
     
     
         46 . The method of  claim 23  wherein the disorder is depression, the first compound is the compound of Formula (I):  
       
         
           
           
               
               
           
         
         and the second compound is fluoxetine.