The non-dihydropyridine L-type voltage-sensitive calcium channel activator FPL 64176 enhances K(+)-evoked efflux of [3H]norepinephrine from rat neocortical slices.
The non-dihydropyridine FPL 64176 (methyl-2,5-dimethyl-4-(2-phenylmethyl)benzoyl-[1-H]pyrrole-3-carboxy la te) was tested for an interaction with neuronal L-type voltage-sensitive calcium channels (L-VSCCs) by using a [3H]isradipine ([3H]ISR) binding assay, and for its ability to enhance K(+)-evoked [3H]norepinephrine ([3H]NE) release from rat neocortical slices. The classical L-VSCC activator, the dihydropyridine (DHP) BAY K 8644, was also used for comparative purposes. FPL 64176 and BAY K 8644 both produced a similar concentration-dependent enhancement of 15 mM K(+)-evoked [3H]NE release which could be completely blocked by the L-VSCC blocker ISR (0.1 microM). FPL 64176, in contrast to BAY K 8644, was a very weak inhibitor of [3H]ISR binding to L-VSCCs. These findings indicate that FPL 64176 is a novel non-dihydropyridine L-VSCC activator, most probably by acting on a site different from the DHP binding site.
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Department of Neuroscience, Purke-Davis Pharmaceutical Research, Warner-Lambert Co., Ann Arbor, MI 48106-1047.
Dooley
D J
DJ
Feuerstein
T J
TJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D017275:Isradipine / Q000378:metabolism; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D015220:Calcium Channels; D011758:Pyrroles; D014316:Tritium; C071658:FPL 64176; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011188:Potassium; D009638:Norepinephrine; D017275:Isradipine