Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists
Journal of Medicinal Chemistry2009Vol. 52(8), pp. 2493–2505
Citations Over TimeTop 25% of 2009 papers
Dramane I. Lainé, Brent W. McCleland, Sonia Thomas, Christopher E. Neipp, Brian Underwood, Jérémy Dufour, Katherine L. Widdowson, Michael R. Palovich, Frank E. Blaney, James J. Foley, Edward F. Webb, Mark A. Luttmann, Miriam Burman, Kristen E. Belmonte, M Salmon
Abstract
A novel 4-hydroxyl(diphenyl)methyl substituted quinuclidine series was discovered as a very promising class of muscarinic antagonists. The structure-activity relationships of the connectivity of the diphenyl moiety to the quinuclidine core and around the ring nitrogen side chain are described. Computational docking studies using an homology model of the M(3) receptor readily explained the observed structure-activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M(3) antagonist with a very long in vivo duration of bronchoprotection.
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