Interaction of ibogaine with human a3b4 nicotinic receptors in different conformational states

Ibogaine inhibits calcium influx through human α3β4 nicotinic acetylcholine receptors with roughly nine times higher potency than phencyclidine (PCP). Radioligand binding shows ibogaine binds to a single site on the receptor with a dissociation constant of 0.46 μM, and it has slightly higher affinity for desensitized receptors than for resting ones. Docking studies indicate both compounds interact with a binding domain between the serine (position 6′) and valine/phenylalanine (position 13′) rings, primarily through van der Waals contacts, consistent with the measured enthalpic contribution. Entropic contributions suggest local conformational changes upon binding.

Study at a glance

Abstract

The interaction of ibogaine and phencyclidine (PCP) with human (h) α3β4 nicotinic acetylcholine receptors (AChRs) in different conformational states was determined using radioligand binding assays, Ca 2+ influx detections, thermodynamic and kinetic measurements. The results show that ibogaine inhibits (±)‐epibatidine‐induced Ca 2+ influx in hα3β4 AChRs with ~9‐fold higher potency than PCP, [ 3 H]ibogaine binds to a single site in hα3β4 with relatively high affinity ( K d = 0.46 ± 0.006 μM), and ibogaine has slightly higher affinity for desensitized than resting hα3β4 AChRs, compared with PCP. These results correlate with the docking studies suggesting that ibogaine and PCP interact with a binding domain between the serine (position 6′) and valine/phenylalanine (position 13′) rings. This interaction is mediated mainly by van der Waals contacts, which is in agreement with the observed enthalpic contribution determined by non‐linear chromatography. Calculated entropic contribution also indicates local conformational changes. Research support came from the Science Foundation Arizona and Stardust Foundation.