Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists

• Published in: Journal of medicinal chemistry 2009-04, Vol.52 (8), p.2493-2505
• Main Authors: Lainé, Dramane I, McCleland, Brent, Thomas, Sonia, Neipp, Christopher, Underwood, Brian, Dufour, Jeremy, Widdowson, Katherine L, Palovich, Michael R, Blaney, Frank E, Foley, James J, Webb, Edward F, Luttmann, Mark A, Burman, Miriam, Belmonte, Kristen, Salmon, Michael
• Format: Article
• Language: English
• Subjects: Animals; Benzhydryl Compounds - chemical synthesis; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological Availability; Bronchi - drug effects; Bronchi - physiology; Bronchoconstriction - drug effects; Bronchodilator Agents - chemical synthesis; Bronchodilator Agents - chemistry; Bronchodilator Agents - pharmacology; Calcium - metabolism; CHO Cells; Cricetinae; Cricetulus; Humans; In Vitro Techniques; Mice; Models, Molecular; Muscle Contraction; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Quinuclidines - chemical synthesis; Quinuclidines - chemistry; Quinuclidines - pharmacology; Radioligand Assay; Rats; Receptor, Muscarinic M3 - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801601v

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 M3 receptor readily explained the observed structure−activity relationship of the various compounds. Compound 14o was identified as a very potent, slowly reversible M3 antagonist with a very long in vivo duration of bronchoprotection.