The Discovery of Novel α 2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening

Most α -AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α -AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α -AR agonists, we performed virtual screening for human α -AR and α -AR to find α -AR agonists with higher selectivity. Compound P300-2342 and its three analogs significantly decreased the locomotor activity of mice ( < 0.05). Furthermore, P300-2342 and its three analogs inhibited the binding of [ H] Rauwolscine with IC values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α -AR and α -AR. In α -AR-HEK293 cells, P300-2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300-2342 activated α -AR with coupling to the Gαi/o pathway but without Gαs coupling. P300-2342 exhibited no agonist but slight antagonist activities in α -AR. Similar results were obtained for the analogs of P300-2342. The docking results showed that P300-2342 formed π-hydrogen bonds with Y394, V114 in α -AR, and V93 in α -AR. Three analogs of P300-2342 formed several π-hydrogen bonds with V114, Y196, F390 in α -AR, and V93 in α -AR. We believe that these molecules can serve as leads for the further optimization of α -AR agonists with potentially few side effects.