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Cyclohexylmethylpiperidinyltriphenylpropioamide: A Selective Muscarinic M 3 Antagonist Discriminating against the Other Receptor Subtypes

2002; American Chemical Society; Volume: 45; Issue: 4 Linguagem: Inglês

10.1021/jm010480k

1520-4804

Yufu Sagara, Takeshi Sagara, Toshiaki Mase, Toshifumi Kimura, Tomoshige Numazawa, Toru Fujikawa, Kazuhito Noguchi, Norikazu Ohtake,

Pharmacological Receptor Mechanisms and Effects

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).