Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.

18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction.