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J Med Chem. 2006 Sep 21;49(19):5653-63.

Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity.

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Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.


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 M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) 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 M(3) selective antagonist that had >100-fold selectivity versus the M(1), M(2), M(4), and M(5) receptors (M(3): K(i) = 0.30 nM, M(1)/M(3) = 570-fold, M(2)/M(3) = 1600-fold, M(4)/M(3) = 140-fold, M(5)/M(3) = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M(3) antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M(3) receptors.

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