Carbazole and tetrahydro-carboline derivatives as dopamine D receptor antagonists with the multiple antipsychotic-like properties.

Dopamine D receptor (DR) is implicated in multiple psychotic symptoms. Increasing the DR selectivity over dopamine D receptor (DR) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as DR selective ligands. Through a structure-based virtual screen, ZLG-25 (DR  = 685 nmol/L; DR  > 10,000 nmol/L) was identified as a novel DR selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel DR-selective analogs with tetrahydro--carboline or tetrahydro--carboline core. Further functional studies showed that most derivatives acted as hDR-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that and could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.