title: Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations.
abstract: The pharmacological, radioligand binding, and electrophysiological properties of FPL 64176, a new nondihydropyridine Ca2+ channel activator, were studied in rat tail artery, cardiac membranes, and A7r5 smooth muscle cells. FPL 64176 induced a contractile response, with an EC50 value of 2.11 x 10(-7) M. The maximum tension response to FPL 64176 was approximately 2-fold higher than that to (S)-Bay K 8644. FPL 64176 showed no significant inhibitory activity at concentrations up to 10(-5) M. The Ca2+ channel antagonists nifedipine, verapamil and diltiazem noncompetitively antagonized and completely relaxed the responses induced by FPL 64176. IC50 values of these three drugs were 5.22 x 10(-9), 1.31 x 10(-7), and 1.95 x 10(-7) M, respectively, for relaxing submaximum contractile responses to FPL 64176 (5 x 10(-7) M). The washout time for FPL 64176 was about 40 min, which was much longer than that for (S)-Bay K 8644 (within 1 min). FPL 64176 weakly inhibited (+)-[3H]PN 200-110, [3H]D888, and [3H]TA-3090 binding in rat cardiac membranes, with IC50 values of 1.04 x 10(-5) M and 7.03 x 10(-6) M for inhibition of (+)-[3H]PN 200-110 and [3H]TA-3090 binding, respectively, and with 23% inhibition of [3H]D888 binding at a FPL 64176 concentration of 1 x 10(-5) M. Dissociation kinetics of the three radioligands were allosterically accelerated by FPL 64176. Electrophysiological studies on the A7r5 smooth muscle cell line directly confirmed a large (approximately 14-fold) stimulatory effect on L-type Ca2+ current amplitude. The results suggest that FPL 64176 is a new type of Ca2+ channel activator with higher efficacy and a mechanism and site of action that are distinct from those for (S)-Bay K 8644.
authors.affiliation: Department of Biochemical Pharmacology, School of Pharmacy, State University of New York, Buffalo 14260.
authors.forename: W
authors.initials: W
authors.lastname: Zheng
authors.forename: D
authors.initials: D
authors.lastname: Rampe
authors.forename: D J
authors.initials: DJ
authors.lastname: Triggle
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000378:metabolism; D004110:Diltiazem / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D009206:Myocardium / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects; D014700:Verapamil / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D011758:Pyrroles; C071658:FPL 64176; C056595:clentiazem; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C043184:4-desmethoxyverapamil; D014700:Verapamil; D004110:Diltiazem; D011188:Potassium; D017275:Isradipine