第十五届海洋药物学术年会暨2021国际海洋药物研讨会

64 / 2021-10-10 17:33:48

Identification of Novel GPR52 Agonists Based on an Indole Alkaloid Scaffold

GPR52,Indole Alkaloid,neuropsychiatric diseases

G-protein-coupled receptor 52 (GPR52) is a highly conserved, brain-specific, G_s-coupled orphan GPCR involving in a number of cAMP-dependent physiological and pathological processes. The activation of GPR52 could benefit the treatment of schizophrenia, cognitive impairment, psychiatric disorders, and other human neurological disease. GPR52 is emerging as a promising target for the treatment of neuropsychiatric diseases. Due to the unknown of the endogenous ligands of GPR52, there is a great challenge to develop GPR52 agonists and none of the current developed GPR52 agonist had entered into clinical tries. In order to serve the unmet medical needs, we carried out the studies on the chemical synthesis, pharmacological evaluation, and molecular docking of an indole alkaloid scaffold leading to the identification of a series of 1-(pyrimidin-4-yl)indoline-4-carboxamide analogues as nanomolar range potency GPR52 agonists. Among them, compound 2 stood out as a potent and efficacy GPR52 agonist with EC₅₀ of 135 nM and E_max of 136%. A broad-panel counter study of compound 2 shown that it had an excellent target specificity. Further studies indicated that compound 2 displayed good physicochemical properties, in vivo pharmacokinetic and good brain permeability. Molecular docking studies of compound 2 and GPR52 suggested that the binding model was consist of three critical hydrogen bonds and an π−π stacking. In vivo studies exhibited that compound 2 significantly inhibited amphetamine-induced psychotic-like activity at a dose of 3 mg/kg. Taken together, the GPR52 agonists provide an important tool to investigate the activation of GPR52 and a potential therapy strategy for the treatment of neuropsychiatric diseases.