Functionally selective ligands of dopamine D
The present invention relates to novel functionally selective ligands of dopamine D 2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D 2 receptors.
1. A compound of formula I:
wherein m is 1;
n is 0, 1, or 2;
q is 1 or 2;
X is O, NH, or CH 2 ;
Y is N;
Z is C, CH, CH 2 , cycloalkyl, aryl, or heteroaryl;
is a single, double, or triple bond as valencies permit;
Ar 1 is a substituted monocyclic or an unsubstituted or substituted bicyclic aryl or an unsubstituted or substituted monocyclic or bicyclic heteroaryl; and
Ar 2 is 3,4-dihydroquinolin-2(1H)-one, 3,4-dihydro-1,8-naphthyridin-2(1H)-one, quinolin-2(1H)-one, 3,4-dihydroisoquinolin-1(2H)-one, benzo[d]thiazole, 1H-benzo[d]imidazol-2(3H)-one, 1H-indazole, or benzo[d]oxazol-2(3H)-one;
or a pharmaceutically acceptable salt or optical isomer thereof.
2. The compound of claim 1 , having the structure of formula III:
wherein n is 0, 1, or 2;
X is O, NH, or CH 2 ;
Y is N;
Ar 1 is a substituted monocyclic or an unsubstituted or substituted bicyclic aryl or an unsubstituted or substituted heteroaryl; and
Ar 2 is 3,4-dihydroquinolin-2(1H)-one, 3,4-dihydro-1,8-naphthyridin-2(1H)-one, quinolin-2(1H)-one, 3,4-dihydroisoquinolin-1(2H)-one, benzo[d]thiazole, 1H-benzo[d]imidazol-2(3H)-one, 1H-indazole, or benzo[d]oxazol-2(3H)-one;
or a pharmaceutically acceptable salt or optical isomer thereof.
3. The compound of claim 1 , having the structure of formula V:
or a pharmaceutically acceptable salt or optical isomer thereof.
4. The compound of claim 1 , selected from the group consisting of:
5. The compound of claim 1 , selected from the group consisting of:
6. The compound of claim 1 , wherein n is 1.
7. The compound of claim 1 , wherein X is O.
8. The compound of claim 1 wherein Ar 2 is:
9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
10. A method of treating a central nervous system disorder associated with D 2 dopamine receptors in a subject, comprising delivering to the subject a therapeutically effective amount of the compound of claim 1 , wherein the disorder associated with D 2 dopamine receptors is a disorder having a psychosis component, Parkinson's disease, pituitary adenoma, prolactinoma, or galactorrhea.
11. The method of claim 10 , wherein the disorder associated with D 2 dopamine receptors is selected from the group consisting of schizophrenia, schizoaffective disorder, schizophreniform disorder, bipolar disorder, mania, manic psychosis, Tourette's syndrome and Tourette-like disorders, obsessive-compulsive disorder, depression with psychotic features, and psychosis not otherwise specified (Psychosis NOS).