Interaction of 18-methoxycoronaridine with nicotinic acetylcholine receptors in different conformational states

Hugo R. Arias, Avraham Rosenberg, Dominik Feuerbach, Katarzyna M. Targowska-Duda, Ryszard Maciejewski, Krzysztof Jozwiak, Ruin Moaddel, Stanley D. Glick, Irving W. Wainer

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The interaction of 18-methoxycoronaridine (18-MC) with nicotinic acetylcholine receptors (AChRs) was compared with that for ibogaine and phencyclidine (PCP). The results established that 18-MC: (a) is more potent than ibogaine and PCP inhibiting (±)-epibatidine-induced AChR Ca2+ influx. The potency of 18-MC is increased after longer pre-incubation periods, which is in agreement with the enhancement of [3H]cytisine binding to resting but activatable Torpedo AChRs, (b) binds to a single site in the Torpedo AChR with high affinity and inhibits [3H]TCP binding to desensitized AChRs in a steric fashion, suggesting the existence of overlapping sites. This is supported by our docking results indicating that 18-MC interacts with a domain located between the serine (position 6′) and valine (position 13′) rings, and (c) inhibits [3H]TCP, [3H]ibogaine, and [3H]18-MC binding to desensitized AChRs with higher affinity compared to resting AChRs. This can be partially attributed to a slower dissociation rate from the desensitized AChR compared to that from the resting AChR. The enthalpic contribution is more important than the entropic contribution when 18-MC binds to the desensitized AChR compared to that for the resting AChR, and vice versa. Ibogaine analogs inhibit the AChR by interacting with a luminal domain that is shared with PCP, and by inducing desensitization.

Original languageEnglish
Pages (from-to)1153-1163
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1798
Issue number6
DOIs
Publication statusPublished - 1 Jun 2010
Externally publishedYes

    Fingerprint

Keywords

  • 18-Methoxycoronaridine
  • Conformational state
  • Ibogaine analog
  • Nicotinic acetylcholine receptor
  • Noncompetitive antagonist

Cite this