Identification of novel benzimidazole series of potent and selective ORL1 antagonists

A structurally novel ORL1 selective antagonist with a (piperazin-1-yl)benzimidazole scaffold was identified. Among them, an analogue 28 exhibited sub-nanomolar antagonistic activity. Structure–activity studies on benzimidazole lead 1 obtained from library screening led to the discovery of potent and selective ORL1 antagonist 28, 5-chloro-2-[(1-ethyl-1-methylpropyl)thio]-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1 H-benzimidazole, which is structurally distinct from conventional non-peptide antagonists known to date.