Lipophilic amino alcohols with calcium channel blocking activity

A series of novel lipophilic amino alcohols, analogs of the anticholinergic drug vesamicol, were evaluated for Ca2+ channel blocking activity. The effects of these drugs on depolarization-induced intracellular free Ca2+ concentration ([Ca2+]i) transients were examined in single NG108-15 cells and dorsal root ganglion (DRG) neurons in culture. [Ca2+] was recorded with the Ca2+ indicator Indo-1 and a dual emission microfluorimeter. Structure-activity studies indicated that features required for Ca2+ channel blocking activity were distinct from those required for anticholinergic activity. In particular, the Ca2+ channel blocking activity was insensitive to the configuration at the chiral center, whereas the anticholinergic activity was clearly enantioselective. One of the most active compounds, 3-(3-bromophenyl)-2-hydroxy-1-[1-(4-phenylpiperidinyl)]propane (2b), was characterized in more detail. This compound inhibited the dihydropyridine-sensitive Ca2+ channel response in NG108-15 cells, evoked by depolarization with 50 mM K+, with an IC50 of 5 microM. Field potential stimulation of DRG neurons elicited [Ca2+]i transients mediated by at least three Ca2+ channel subtypes; compound 2b inhibited the entire Ca2+ channel response with an IC50 of 1 microM. A key element required for Ca2+ channel blocking activity was the presence of an electron withdrawing substituent on the pendant phenyl ring. Modification of the amino alcohol structure may lead to more potent compounds with broad spectrum Ca2+ channel blocking activity. These structures provide a new chemical starting point for the development of Ca2+ antagonists.