Interaction of Novel Ibogaine Analogs With The Human α3β4 Nicotinic Receptor

Abstract

This work is an attempt to characterize the binding site and the inhibitory activity of ibogaine analogs on the human α3β4 nicotinic acetylcholine receptor (hα3β4). In this regard, we used [3H]ibogaine equilibrium binding and Scatchard-plots, [3H]ibogaine and [3H]epibatidine competition binding, and ibogaine-induced inhibition of Ca2+ influx approaches. The results indicate that: (1) there is one high-affinity binding site for [3H]ibogaine, (2) ibogaine inhibits the hα3β4 with higher potency than that for the α1β2γδ AChR, (3) ibogaine interacts with different conformations of the hα3β4 with the indicated affinity (or potency) sequence: Desensitized > Resting > Open, (4) [3H]ibogaine competition experiments indicate that ibogaine and 18-MAC, among ibogaine analogs, and imipramine and dextromethorphan, among other known noncompetitive antagonists, have the highest affinities for the hα3β4 ion channel, and (5) [3H]epibatidine competition experiments indicate that ibogaine analogs interact with the agonist sites with very low affinities. Interaction of 18-MAC with the hα3β4 ion channel could be important for its anti-addictive property.