1053610-06-2Relevant articles and documents
Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity
Sagara, Yufu,Sagara, Takeshi,Uchiyama, Minaho,Otsuki, Sachie,Kimura, Toshifumi,Fujikawa, Toru,Noguchi, Kazuhito,Ohtake, Norikazu
, p. 5653 - 5663 (2007/10/03)
Identification of a novel class of potent and highly selective M 3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M3 selective antagonist that had > 100-fold selectivity versus the M1, M 2, M4, and M5 receptors (M3: K i = 0.30 nM, M1/M3 = 570-fold, M 2/M3 = 1600-fold, M4/M3 = 140-fold, M5/M3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M3 receptors.
