Selective effects of a 4-oxystilbene derivative on wild and mutant neuronal chick α7 nicotinic receptor

L. Maggi, E. Palma, F. Eusebi, M. Moretti, B. Balestra, F. Clementi, C. Gotti

Research output: Contribution to journalArticle

Abstract

1. We assessed the pharmacological activity of triethyl-(β-4-stilbenoxy-ethyl) ammonium (MG624), a drug that is active on neuronal nicotinic receptors (nicotinic AChR). Experiments on the major nicotinic AChR subtypes present in chick brain, showed that it inhibits the binding of [125I]-αBungarotoxin (αBgtx) to the α7 subtype, and that of [3H]-epibatidine (Epi) to the α4β2 subtype, with K(i) values of respectively 106 nM and 84 μM. 2. MG624 also inhibited ACh elicited currents (I(ACh)) in the oocyte-expressed α7 and α4β2 chick subtypes with half-inhibitory concentrations (IC50) of respectively 109 nM and 3.2 μM. 3. When tested on muscle-type AChR, it inhibited [125I]-αBgtx binding with a K(i) of 32 μM and ACh elicited currents (I(ACh)) in the oocyte-expressed α1β1γδ chick subtype with an IC50 of 2.9 μM. 4. The interaction of MG624 with the α7 subtype was investigated using an α7 homomeric mutant receptor with a threonine-for-leucine 247 substitution (L247T α7). MG624 did not induce any current in oocytes expressing the wild type α7 receptor, but did induce large currents in the oocyte-expressed L247T α7 receptor. The MG624 elicited current (I(MG624)) has an EC50 of 0.2 nM and a Hill coefficient nH of 1.9, and is blocked by the nicotinic receptor antagonist methyllycaconitine (MLA). 5. These binding and electrophysiological studies show that MG624 is a potent antagonist of neuronal chick α7 nicotinic AChR, and becomes a competitive agonist following the mutation of the highly conserved leucine residue 247 located in the M2 channel domain.

Original languageEnglish
Pages (from-to)285-295
Number of pages11
JournalBritish Journal of Pharmacology
Volume126
Issue number1
DOIs
Publication statusPublished - 1999

Keywords

  • αBungarotoxin
  • Chick
  • Epibaridine
  • Methyllycaconitine
  • MG624
  • Muscle nicotinic receptors
  • Neuronal nicotinic receptors
  • Oocytes
  • Subtypes

ASJC Scopus subject areas

  • Pharmacology

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