Ibogaine, a noncompetitive inhibitor of serotonin transport, acts by stabilizing the cytoplasm-facing state of the transporter.

Ibogaine, a hallucinogenic alkaloid reported to help treat addiction, inhibits the serotonin transporter (SERT) through a noncompetitive mechanism, reducing the maximum transport rate (Vmax) with little effect on serotonin's binding affinity (Km). It also competitively blocks binding of a cocaine analog to SERT, increasing the apparent dissociation constant (KD) without altering the number of binding sites (Bmax). Ibogaine increases reactivity of cysteine residues in the proposed cytoplasmic permeation pathway of SERT but slows reactivity of cysteines in the extracellular pathway. These findings suggest ibogaine binds to and stabilizes the SERT state from which serotonin dissociates into the cytoplasm, opposite to cocaine's action, which stabilizes the state that binds extracellular serotonin.

Study at a glance

Abstract

Ibogaine, a hallucinogenic alkaloid with purported anti-addiction properties, inhibited serotonin transporter (SERT) noncompetitively by decreasing V(max) with little change in the K(m) for serotonin (5-HT). Ibogaine also inhibited binding to SERT of the cocaine analog 2beta-2-carbomethoxy-3-(4-[(125)I]iodophenyl)tropane. However, inhibition of binding was competitive, increasing the apparent K(D) without much change in B(max). Ibogaine increased the reactivity of cysteine residues positioned in the proposed cytoplasmic permeation pathway of SERT but not at nearby positions out of that pathway. In contrast, cysteines placed at positions in the extracellular permeation pathway reacted at slower rates in the presence of ibogaine. These results are consistent with the proposal that ibogaine binds to and stabilizes the state of SERT from which 5-HT dissociates to the cytoplasm, in contrast with cocaine, which stabilizes the state that binds extracellular 5-HT.