Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties.
- Author:
Zhongtang LI
1
;
Fan FANG
1
;
Yiyan LI
1
;
Xuehui LV
1
;
Ruqiu ZHENG
1
;
Peili JIAO
1
;
Yuxi WANG
1
;
Guiwang ZHU
1
;
Zefang JIN
1
;
Xiangqing XU
2
;
Yinli QIU
2
;
Guisen ZHANG
3
;
Zhongjun LI
1
;
Zhenming LIU
1
;
Liangren ZHANG
1
Author Information
- Publication Type:Journal Article
- Keywords: Antipsychotic; Bitopic ligand; Carbazole derivatives; Dopamine D3 receptor; Tetrahydro-carboline
- From: Acta Pharmaceutica Sinica B 2023;13(11):4553-4577
- CountryChina
- Language:English
- Abstract: Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-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.
