Carbazole and tetrahydro-carboline derivatives as dopamine D(3) receptor antagonists with the multiple antipsychotic-like properties

Dopamine D(3) receptor (D(3)R) is implicated in multiple psychotic symptoms. Increasing the D(3)R selectivity over dopamine D(2) receptor (D(2)R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D(3)R selective ligands. Through a structure-based virtual screen, ZLG-25 (D(3)R K(i) = 685 nmol/L; D(2)R K(i) > 10,000 nmol/L) was identified as a novel D(3)R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD(3)R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b 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 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.