Synthesis and Pharmacological Characterization of Novel Tetrahydropyridine-Based Muscarinic M5 Receptor Antagonists to Investigate the Difference in the SARs of Muscarinic Receptor Subtypes Utilizing Induced Fit Docking Studies.

Many studies and experiments suggest the muscarinic M5 receptor (M5R) as a potential target for the clinical treatment of drug abuse, schizophrenia, or Alzheimer's disease. In the present study, a library containing 39 novel hM5R antagonists based on an arecaidine (tetrahydropyridine) core was synthesized, pharmacologically characterized in radioligand competition binding or mini-G protein assays and analyzed in molecular docking studies to elucidate their binding modes and in vitro characteristics. Compound 56m showed low single-digit nanomolar affinity on hM5R combined with a 17-fold selectivity over hM2R, while compound 81d displayed good affinity on hM5R with a 3- to 12-fold selectivity over the other subtypes. Induced fit docking studies suggest the conserved Y2.60 and hM5R-unique Q45.51 as the responsible amino acids regarding affinity and selectivity.