Methods for treating antipsychotic-induced weight gain
The present invention relates to the discovery of a novel opioid modulator effective in reducing pharmacologically induced weight gain associated with atypical antipsychotic use. The present invention provides methods of reducing antipsychotic induced weight gain, methods for suppressing food intake and reducing ghrelin levels induced by atypical antipsychotic medications in a patient.
1. A method of reducing antipsychotic induced weight gain comprising administering to the patient in need of treatment an effective amount of a compound of Formula I;
wherein, A is chosen from —C(═O)NH 2 and —C(═S)NH 2 ;
R 1 and R 2 are both hydrogen or taken together R 1 and R 2 are ═O;
R 3 is chosen from hydrogen, alkyl, alkenyl, aryl, heterocyclyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 5 is selected from hydrogen, hydroxyl, alkoxy and alkyl;
R 6 is chosen from hydrogen, hydroxy, alkoxy and —NR 10 R 11 ;
or together, R 5 and R 6 form a carbonyl or a vinyl substituent;
R 10 and R 11 are chosen independently from hydrogen and alkyl and aliphatic; and,
represents a single or double bond.
2. The method of claim 1 , wherein said compound of Formula I is selected from a compound of Formula II:
wherein, R 3 , R 4 , R 5 , and R 6 are as defined above.
3. The method according to claim 1 , wherein said compound of Formula I is selected from Table A:
TABLE A
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
4. The method according to claim 1 , wherein the weight gain is induced by administration of an atypical antipsychotic.
5. The method according to claim 1 , wherein said compound is Compound 1:
6. The method of claim 4 , wherein the atypical antipsychotic is selected from the group consisting of olanzapine, clozapine, risperidone, quetiapine, aripiprazole, ziprasidone, and pharmaceutically acceptable salts thereof.
7. The method of claim 6 , wherein the atypical antipsychotic is used in the treatment of schizophrenia, bipolar disorder, dementia, acute mania, major depression and psychotic agitation.
8. A method of reducing Ghrelin level in the gastrointestinal tract comprising the step of administering a compound of Formula I to a patient in need thereof.
9. The method according to claim 8 , wherein said compound of Formula I is Compound 1.
10. A composition comprising an atypical antipsychotic and a compound of Formula I;
wherein, A is chosen from —C(═O)NH 2 and —C(═S)NH 2 ;
R 1 and R 2 are both hydrogen or taken together R 1 and R 2 are ═O;
R 3 is chosen from hydrogen, alkyl, alkenyl, aryl, heterocyclyl and hydroxyalkyl;
R 4 is chosen from hydrogen, hydroxy, amino, alkoxy, C 1 -C 20 alkyl and C 1 -C 20 alkyl substituted with hydroxy or carbonyl;
R 5 is selected from hydrogen, hydroxyl, alkoxy and alkyl;
R 6 is chosen from hydrogen, hydroxy, alkoxy and —NR 10 R 11 ;
or together, R 5 and R 6 form a carbonyl or a vinyl substituent;
R 10 and R 11 are chosen independently from hydrogen and alkyl and aliphatic; and
represents a single or double bond.
11. The composition of claim 10 , wherein said atypical antipsychotic is selected from olanzapine, clozapine, risperidone, quetiapine, aripiprazole, and ziprasidone.
12. The composition of claim 10 , wherein said compound of Formula I is selected from Table A:
TABLE A
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18