Studies on Ca2+ channel antagonists. A 2-diazo-3,3,3-trifluoropropionamide derivative related to verapamil as a potential photoaffinity probe

Abstract

2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-[N-[4-(N-methyl-2-diazo-3,3,3-trifluoropropioniamido)phenethyl]methylamino]valeronitrile (3), a potential photoaffinity probe for Ca2+ channels related to verapamil (1), was prepared from N-methyl-4-nitrophenethylamine (7) and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methanesulfonoxy)valeronitrile (12). Compound 3 showed concentration-dependent negative inotropic effects in rat right myocardial ventricular strips, EC50 = (1.05 .+-. 0.33) .times. 10-7 M (mean .+-. SD), being slightly less potent than gallopamil (2), EC50 = (2.18 .+-. 0.66) .times. 10-8 M. It displaced [3H]gallopamil in myocardial membranes, Ki = (3.76 .+-. 1.55) .times. 10-8 M, compared to 2, Ki = (1.55 .+-. 0.16) .times. 10-8 M. Photoactivation at 265 nm reduced the recoverable binding of [3H]gallopamil to 26% compared to no effect on 2. This agent may be a useful photoaffinity probe to aid in further characterization of Ca2+ channels.