Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M(4) muscarinic acetylcholine receptor agonists.

Abstract We designed and synthesized novel N -sulfonyl-7-azaindoline derivatives as selective M 4 muscarinic acetylcholine receptor agonists. Modification of the N -carbethoxy piperidine moiety of compound 2 , an M 4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1 , a selective M 4 mAChR agonist. Compound 1 showed a highly selective M 4 mAChR agonistic activity with weak hERG inhibition in vitro. A pharmacokinetic study of compound 1 in vivo revealed good bioavailability and brain penetration in rats. Compound 1 reversed methamphetamine-induced locomotor hyperactivity in rats (1–10 mg/kg, po).