Alcohol Clin Exp Res 2002 Jan 01;261:8-18.

Structural requirements of alkanol interaction sites on human alpha 2 beta 4 neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes: effects of linear and branched-chain alkanols.

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BACKGROUND: Nicotine and alcohol are both drugs of abuse that are frequently used concurrently, but little is known about the interactions between these agents at the molecular level. The neuronal subgroup of nicotinic acetylcholine receptors (nAChRs) are members of a neurotransmitter-gated ion channel superfamily and have been used extensively to characterize the interactions of ethanol with these channels. Previous work has shown that both the direction and the magnitude of the modulatory effects of n-alcohols and several fluorinated analogs on nAChRs can be predicted based upon the molecular volume of the alkanol. However, size (molecular volume) is only one of several determinants of binding-site interactions; shape and flexibility of the interacting ligand and/or the site itself (i.e., structural constraints) and alkanol hydrophobicity are also likely to be involved. METHODS: Two-electrode voltage-clamp electrophysiology was used to investigate the effects of alkanols on the alpha2beta4 human neuronal nicotinic acetylcholine receptor ectopically expressed in Xenopus oocytes. RESULTS: ACh-induced currents mediated by alpha2beta4 nAChRs were potentiated by 1- and 2-propanol, whereas 1-pentanol and several branched-chain pentanol isomers only inhibited channel activity. 1-Butanol had a biphasic concentration-response curve, producing a nearly 2-fold increase in current at lower concentrations and >50% inhibition at higher concentrations. Other four-carbon alcohols such as 2-butanol and 2-methyl-1-propanol also facilitated responses at lower concentrations and inhibited at higher concentrations, whereas 2-butene-1-ol and 2-methyl-2-propanol only inhibited responses. The effects of these alkanols on ACh responses were the result of changes in both the potency as well as the efficacy of ACh at these receptors. CONCLUSIONS: Although molecular volume and hydrophobicity both correlate well with the potencies of linear alkanols in modulating the activity of alpha2beta4 nAChRs, these relationships break down almost completely when comparing the structural isomers of these agents. The structure of the interacting alkanol significantly affects the potency and efficacy of alkanols at the nAChR, and this occurs independently of differences in molecular volume and hydrophobicity.

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