Synthesis and biological activity of carboxy verapamil, a new derivative of verapamil.
New analogues of the calcium antagonist verapamil (alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-gamma-aminopropy l] -3,4-dimethylphenyl acetonitrile) were synthesized. Carboxy verapamil (alpha-isopropyl-alpha-[(N-methyl-N-homoveratryl)-gamma -aminopropyl]-3,4-dimethylphenyl acetic acid) was prepared by hydrolysis of the nitrile group of verapamil. Derivatives of carboxy verapamil could be synthesized by coupling substituents onto the carboxylic acid moiety. All syntheses can be prepared on a microscale. The biological activity of carboxy verapamil was compared with that of verapamil by testing their ability to block the isoproterenol-induced slow action potential (APs) in guinea pig papillary muscle. Carboxy verapamil was about 10-fold less potent than verapamil in blocking the slow APs. The IC50 for carboxy verapamil was about 6 X 10(-6) M. Furthermore both drugs had a similar frequency dependency. The effects of carboxy verapamil were rapidly reversed upon washout, suggesting that this drug may act on the external surface of the myocardial plasma membrane. In contrast, verapamil-induced effects are slowly reversed upon washout and it may exert is primary effects on the inner surface of the plasma membrane. Carboxy verapamil, because of its dipolar charge character may not readily penetrate into myocardial cells.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D008297:Male; D010210:Papillary Muscles / Q000502:physiology; D014700:Verapamil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D002121:Calcium Channel Blockers; C043220:carboxyverapamil; D014700:Verapamil