Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists

Abstract We designed and synthesized a series of dihydroquinazolinone derivatives as selective M 1 and M 4 muscarinic acetylcholine receptors agonists. Introduction of the N -carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M 1 and M 4 muscarinic acetylcholine receptors with M 4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED 50  = 3.0 mg/kg, sc).