Differential effects of non-peptidic tachykinin receptor antagonists on Ca2+ channels.
The effects of a range of non-peptidic neurokinin receptor antagonists on dihydropyridine binding at voltage-dependent Ca2+ channels from rat skeletal muscle were studied. As previously reported, the binding studies on dihydropyridine binding sites revealed a temperature-dependency effect of the tachykinin NK1 receptor antagonist (+/-)-CP 96345 ((2S,3S)-cis-2-(diphenylmethyl)-N-((2-methoxyphenyl) methyl)-1-azabicyclo-[2.2.2.]-octan-3-amine) similar to d-cis-diltiazem. Its related homologue CP 99994 ((+)-2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperid ine) was devoid of such activity. However, RP 67580 (perhydroisoindol-4-one-(3aR,7aR)-7,7-diphenyl- 2[1-imino-2-(2-methoxyphenyl)ethyl]) and SR 48968 ((S)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichloro phenyl) butyl]benzamide) (tachykinin NK1 and NK2 receptor antagonists) were also potent inhibitors of [3H]PN 200-110 (Isradipine) binding without temperature dependency, indicating that actions on ion channels may contribute to their pharmacological effects. Furthermore, all the compounds had affinity for the D888 ((-)-devapamil) phenylalkylamine site, indicating that many neurokinin antagonists may have affinity for Ca2+ channels.
Lombet
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A
Department of Molecular and Cellular Biology, Institut de Rcherches Servier, Suresnes, France.
Spedding
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M
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004095:Dihydropyridines / Q000378:metabolism; D066298:In Vitro Techniques; D017275:Isradipine / Q000494:pharmacology*; D009132:Muscles / Q000187:drug effects; D051381:Rats; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D014700:Verapamil / Q000031:analogs & derivatives* / Q000494:pharmacology
D015220:Calcium Channels; D004095:Dihydropyridines; D018039:Receptors, Tachykinin; C038806:1,4-dihydropyridine; C043184:4-desmethoxyverapamil; D014700:Verapamil; D017275:Isradipine