Discovery of novel α2A adrenergic receptor agonists coupling to Gαi/o proteins by virtual screening
10.3867/j.issn.1000-3002.2023.07.188
- Author:
Fengfeng LU
1
;
Huili ZHU
;
Beibei SHI
;
Xiaoxuan WANG
;
Yulei LI
;
Peilan ZHOU
;
Ruibin SU
Author Information
1. State Key Laboratory of Toxicology and Medical Counter-measures,Beijing Key Laboratory of Neuropsychopharma-cology,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China
- Keywords:
α2A adrenergic receptor;
virtual screening;
Gαi/o proteins
- From:
Chinese Journal of Pharmacology and Toxicology
2023;37(7):555-555
- CountryChina
- Language:Chinese
-
Abstract:
Most α2-AR agonists derived from dexme-detomidine have few structure differences between them and have no selectivity for α2A/2B-AR or Gi/Gs,that can lead to the side effect of drugs.To get novel and potent α2A-AR agonists,we built the homology model for human α 2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity.Compound P300-2342 and its 3 analogs sig-nificantly decreased the locomotor activity of mice(P＜0.05).Furthermore,P300-2342 and its 3 analogs inhibited the binding of[3H]rauwolscine to α 2A-AR and α 2B-AR respectively.In α2A-AR-HEK293 cells,P300-2342 decre-ased forskolinstimulatedcAMPpruductionwithoutincreas-ing cAMP pruduction,that indicated the P300-2342 acti-vating α2A-AR coupling with Gαi/o pathway without Gαs coupling.P300-2342 had no agonistic and antagonistic activities on α 2B-AR.Similar results were shown in 3 analogs of P300-2342.The docking results showed that P300-2342 formed the π-hydrogen bonds with Y394,V114 of α2A-AR,and with V93 of α2B-AR.3 analogs of P300-2342 formed several π-hydrogen bonds with V114,Y196,F390 of α 2A-AR and with V93 of α 2B-AR.We believe that these molecules can serve as leads for fur-ther optimization of α2A-AR agonists with potentially few side effects.
