Studies on Ca2+ channel antagonists. A 2-diazo-3,3,3-trifluoropropionamide derivative related to verapamil as a potential photoaffinity probe.
2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-[N-[4-(N-methyl-2-diazo- 3,3,3-trifluoropropionamido)phenethyl]methyl-amino]valeronitril e (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)valeron itrile (12). Compound 3 showed concentration-dependent negative inotropic effects in rat right myocardial ventricular strips, EC50 = (1.05 +/- 0.33) X 10(-7) M (mean +/- SD), being slightly less potent than gallopamil (2), EC50 = (2.18 +/- 0.66) X 10(-8) M. It displaced [3H]gallopamil in myocardial membranes, Ki = (3.76 +/- 1.55) X 10(-8) M, compared to 2, Ki = (1.55 +/- 0.16) X 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.
Theodore
L J
LJ
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Nelson
W L
WL
Dave
B
B
Giacomini
J C
JC
D000345:Affinity Labels; D000818:Animals; D001386:Azides / Q000138:chemical synthesis* / Q000378:metabolism; D001667:Binding, Competitive; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D005711:Gallopamil / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009570:Nitriles / Q000138:chemical synthesis* / Q000378:metabolism; D010777:Photochemistry; D051381:Rats
D000345:Affinity Labels; D001386:Azides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D009570:Nitriles; C062825:2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(N-(4-(N-methyl-2-diazo-3,3,3-trifluoropropionamido)phenethyl)methylamino)valeronitrile; D005711:Gallopamil