Antagonists of alcohol inhibition of cell adhesion

摘要

Increasing evidence suggests that alcohols act within specific binding pockets of selective neuraI proteins: however, antagonists at these sites have not been identified. 1-Alcohols from methanol through 1-butanol inhibit with increasing potency the cell--cell adhesion mediated by the immunoglobuIin cell adhesion molecule L1. An abrupt cutoff exists after 1-butanoI. with 1-pentanol and higher 1-alcohols showing no effect. Here, we demonstrate sur- prisingly strict structural requirements for alcohol inhibition of cell--cell adhesion in L1-transfected NIH 3T3 fibroblasts and in NG108--15 neurobIastoma x glioma hybrid cells treated with BMP-7, an inducer of L1 and neuraI ceIl adhesion molecule. The target site discriminates the tertiary structure of straight-chain and branched-chain alcohols and appears to comprise both a hydro- phobic binding site and an adjacent hydrophilic allosteric site. Modifications,to the 2- and 3-carbon positions of 1-butanol in- creased potency, whereas modifications that restrict movement about the 4-carbon aboIished activity. The effects of ethanol and 1-butanol on cell--cell adhesion were antagonized by 1-pentanol (lC_so = 715 μM) and 1-octanol (lC_5o = 3.6 μM). Antagonism by 1-octanol was complete, reversible, and noncompetitive. 1 -Octanol also antagonized ethanol inhibition of BMP-7 morphogenesis in NG108--15 cells. 1-Octanol and related compounds may prove useful in dissecting the role of altered cell adhesion in ethanol- induced in juiy of the nervous system.