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.
Pace
Christopher J
CJ
Center for Neuropharmacology and Neuroscience, The Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA.
Glick
Stanley D
SD
Maisonneuve
Isabelle M
IM
He
Li-Wen
LW
Jokiel
Patrick A
PA
Kuehne
Martin E
ME
Fleck
Mark W
MW
D019969:Amphetamine-Related Disorders / Q000188:drug therapy*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007050:Ibogaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009021:Morphine Dependence / Q000188:drug therapy*; D018733:Nicotinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000502:physiology; D012201:Reward; D012646:Self Administration; D030014:Tabernaemontana
D018733:Nicotinic Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D007050:Ibogaine; C103345:18-methoxycoronaridine