DIFFERENTIAL-EFFECTS OF NONPEPTIDIC 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-(diphenyl-methyl)-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 (perhydroiso-indol-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-dichlorophenyl)butyl]benzamide) (tachykinin NK1 and NK2 receptor antagonists) were also potent inhibitors of [H-3]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.