Iptakalim as a human nicotinic acetylcholine receptor antagonist

Nicotinic acetylcholine receptors (nAChRs) play many critical roles in nervous system function and have been implicated in a variety of diseases. Drugs acting at nAChRs, perhaps in nAChR subtype-selective manners, can be used to dissect receptor function and perhaps as medications. In the present study, we used patch-clamp whole-cell recording and pharmacological manipulations to evaluate effects of iptakalim hydrochloride (Ipt), which is a drug reported to act as an ATP-sensitive potassium (K(ATP)) channel opener, on selected human nAChRs heterologously expressed in the native nAChR-null SH-EP1 human epithelial cell line. Ipt reduced both peak and steady-state whole-cell current amplitudes mediated by human alpha4beta2-nAChRs in response to nicotinic agonists. It also accelerated current decay, caused a decline in apparent efficacy of agonists, and acted in voltage- and use-dependent manners at alpha4beta2-nAChRs. These findings and the inability of Ipt to block radiolabeled epibatidine binding to alpha4beta2-nAChRs suggest a noncompetitive mechanism of antagonism. Other studies discount effects of Ipt on nAChR internalization or involvement of K(ATP) channels in Ipt-induced inhibition of alpha4beta2-nAChR function. By comparison, alpha7-nAChRs were less sensitive than alpha4beta2-nAChRs to Ipt acting as an antagonist. Thus, alpha4beta2-nAChRs are among the molecular targets of Ipt, which has utility as a tool in functional characterization and pharmacological profiling of nAChRs.