Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties
ACTA PHARMACEUTICA SINICA B(2023)
Abstract
Dopamine D-3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D-2 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 K-i = 685 nmol/L; D2R K-i > 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-beta-carboline or tetrahydro-gamma-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.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
MoreTranslated text
Key words
Dopamine D-3 receptor,Carbazole derivatives,Tetrahydro-carboline,Bitopic ligand,Antipsychotic
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined