Alcohol modulation of drug binding to the channel sites of the nicotinic acetylcholine receptor

E. F. Ei-Fakahany, E. R. Miller, M. A. Abbassy, A. T. Eldefrawi, M. E. Eldefrawi

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The interactions of aliphatic alcohols (C2-C10) and 1-naphthol with the nicotinic acetylcholine receptor channel in Torpedo electric organ membranes were studied and alcohols were found to have two effects. At low concentrations, they increased the initial rate of binding of [3H]perhydrohistrionicotoxin, [3H]phencyclidine and [3H]imipramine to the channel sites of the receptor in a concentration-dependent manner and at high concentrations this potentiation was reduced, and they also inhibited the carbamylcholine (carb)-mediated increase in the rate of binding of the three 3H-labeled ligands studied. There was excellent correlation of the potencies of the alcohols in these two effects with their membrane/buffer partition coefficients. However, acetylation of 1-naphthol, which increases its hydrophobicity, reduced dramatically its effect on channel drug binding. The inhibition of carb-stimulated channel drug binding by alcohols was dependent upon carb concentration, such that ethanol inhibited the effect only at high carb concentrations, while it potentiated it at low carb concentrations. Pretreatment of the membranes with Naja α-toxin did not alter the alcohol effects and ethanol did not inhibit [3H]acetylcholine binding to the receptor sites. It is suggested that at low concentrations, alcohols potentiate channel drug binding and increase the affinity of carb for the receptor sites by binding to a third kind of site, an 'alcohol site' on the receptor/channel molecule, which may be at the domains of the proteins embedded in the lipid bilayer.

Original languageEnglish (US)
Pages (from-to)289-296
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Apr 14 1983

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