Design, Synthesis, and in Vitro Agonist Activity Evaluation of Novel 5-(Pyridin-4-yl)-1H-Pyrrole-2-Carboxamides GPR52 Agonists

To discover novel and potent GPR52 agonists, compound 4 was used as the hit compound, and a scaffold hopping strategy was applied in this study. Eight novel GPR52 agonists were synthesized via nucleophilic substitution, Suzuki coupling, and amide condensation. Their in vitro GPR52 agonist activities were then evaluated. Among them, the agonistic activity of compound 6g (activation rate of 93%) is closest to that of the positive control compound 4 (activation rate of 100%). Molecular docking studies revealed the binding mode of compound 6g. The terminal hydroxyl group formed hydrogen bonds with residues Asp38 and Thr44. The pyridine ring engaged in a π-π stacking interaction with Phe300. The benzene ring extended into a narrow hydrophobic pocket, forming hydrophobic interactions. These findings provide a solid foundation for the development of novel, highly efficacious, and low-toxicity antipsychotic drugs.