Interaction of ibogaine analogs with the nicotinic acetylcholine receptor
Krzysztof Jóźwiak, Ruin Moaddel, Irving W. Wainer, Hugo Arias‐pulido
The FASEB Journal April 1, 2008 Peer reviewed DOI: 10.1096/fasebj.22.2_supplement.620 via OpenAlex
Summary
The study identifies a high-affinity binding site for the ibogaine analog 18-methoxycoronaridine (18-MC) on the nicotinic acetylcholine receptor (AChR) in its desensitized state, with a dissociation constant of 0.23 ± 0.04 μM. The binding affinity for various 18-MC congeners varies significantly between desensitized and resting states, indicating that these compounds can modulate receptor activity. Additionally, the study suggests that ibogaine congeners may inhibit AChR by promoting desensitization.
Study at a glance
| Population | Torpedo AChR membranes |
|---|---|
| Key finding | There is one high-affinity binding site for 18-MC in the desensitized AChR with a dissociation constant of 0.23 ± 0.04 μM. |
Abstract
PURPOSE: Characterization of the binding sites for ibogaine analogs on the nicotinic acetylcholine receptor (AChR) in the resting and desensitized states. METHODS: [ 3 H]18‐methoxycoronaridine ([ 3 H]18‐MC) Scatchard‐plots using Torpedo AChR membranes, [ 3 H]TCP (a well characterized noncompetitive antagonist) competition binding experiments and Schild‐type analysis, analog‐induced binding modulation of the agonist [ 3 H]cytisine, and molecular modeling of the Torpedo AChR ion channel and molecular docking of 18‐MC. RESULTS: (1) there is one (0.86 ± 0.13) high‐affinity (K d = 0.23 ± 0.04 μM) binding site for [ 3 H]18‐MC in the desensitized AChR; (2) the affinity (in μM) of each 18‐MC congener for the [ 3 H]TCP locus in the desensitized state follows the sequence: 18‐MC (0.17 ± 0.01) > 2‐methoxyethyl‐18‐MC (1.3 ± 0.1) ~ 18‐methylaminocoronaridine (1.3 ± 0.2) > (+)coronaridine (3.2 ± 0.4) ~ albifloranine (3.2 ± 0.3) > ibogaine (5.4 ± 0.3). Whereas, the affinity sequence in the resting state is: 18‐MC (12 ± 1) > 18‐methylaminocoronaridine (20 ± 2) > (+)coronaridine (48 ± 5) > 2‐methoxyethyl‐18‐MC (82 ± 8) > ibogaine (182 ± 17) > albifloranine (252 ± 24); (3) Schild‐type analysis suggests that 18‐MC interacts with the TCP site in a steric manner; (4) [ 3 H]cytisine binding is enhanced by the 18‐MC congeners when the AChR is in the resting but activable state, but not in the desensitized state; and (5) 18‐MC interacts with a domain formed between valine (position 13’) and leucine (position 9’) rings. CONCLUSIONS: binding and modeling results indicate that the 18‐MC binding site overlaps the TCP locus located in the middle of the desensitized ion channel, and that ibogaine congeners may inhibit the AChR by inducing the desensitization process.