Synthesis and cardiac electrophysiological activity of 2- and 3-[(substituted phenyl)alkyl]quinuclidines. Structure-activity relationships.
The syntheses and cardiac electrophysiological effects of 21 2- and 3-substituted quinuclidines and some quaternary ammonium derivatives are described. The 2-substituted quinuclidines 2-8 were prepared by alkylation of 2-methylene-3-quinuclidinone. The Wittig reaction with 3-quinuclidinone afforded the 3-substituted derivative 9, which was subsequently converted to 10 and 11. The electrophysiological profiles of the compounds were determined in canine cardiac Purkinje fibers and ventricular muscle strips. The 3-[(substituted phenyl)alkyl]quinuclidines selectively increased action potential duration (Vaughan Williams class III activity). In the 2-substituted series some of the compounds both increased action potential duration and decreased conduction velocity (class I activity). For some of the 2-substituted quinuclidines, appropriate substitution of the phenyl ring was shown to be a requirement for significant class III electrophysiological activity. Selected compounds were efficacious in a programmed electrical stimulation model in the anesthetized dog.
Morgan
T K
TK
Berlex Laboratories, Inc., Cedar Knolls, New Jersey 07927.
Lis
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R
Marisca
A J
AJ
Argentieri
T M
TM
Sullivan
M E
ME
Wong
S S
SS
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008968:Molecular Conformation; D011812:Quinuclidines / Q000138:chemical synthesis* / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D011812:Quinuclidines