Effects of McN-6186 on voltage-dependent Ca++ channels in heart and pituitary cells

McN-6186 (N-[2-(3,5-dimethoxyphenyl)ethyl]-5-methoxy-alpha-methyl-2 -(phenylethynyl) benzeneethanamine hydrochloride is a compound structurally distinct from other Ca++ channel ligands. McN-6186 showed some stimulation of 1,4-dihydropyridine-sensitive Ca++ uptake in neonatal rat ventricular cells at concentrations of 1 and 3 nM. At higher concentrations McN-6186 inhibited this uptake in rat ventricular cells at concentrations approximately 100-fold less than those needed to block the corresponding Ca++ uptake in rat anterior pituitary (GH3) cells. McN-6186 (2 microM) inhibited L-type Ca++ channel current in neonatal rat ventricular cells in a voltage-dependent manner while having little or no effect on this current in GH3 cells. In some ventricular cells tested, the T-type Ca++ current was also blocked by 2 microM McN-6186. McN-6186 inhibited (+)-[3H]PN200-110 binding in rat cardiac membranes with an IC50 value of 1.45 X 10(-7) M and a shallow Hill slope (nH = 0.42). It is concluded that McN-6186 blocks L-type Ca++ channels in heart cells preferentially to those found in GH3 cells. Furthermore, McN-6186 may have other sites and mechanisms of action in addition to L-type Ca++ channel blockade.