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Identification of a Novel 4-Aminomethylpiperidine Class of M 3 Muscarinic Receptor Antagonists and Structural Insight into Their M 3 Selectivity

2006; American Chemical Society; Volume: 49; Issue: 19 Linguagem: Inglês

10.1021/jm051205r

1520-4804

Yufu Sagara, Takeshi Sagara, Minaho Uchiyama, Sachie Otsuki, Toshifumi Kimura, Toru Fujikawa, Kazuhito Noguchi, Norikazu Ohtake,

Adenosine and Purinergic Signaling

Identification of a novel class of potent and highly selective M3 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, M2, M4, and M5 receptors (M3: Ki = 0.30 nM, M1/M3 = 570-fold, M2/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.