Antagonists of alcohol inhibition of cell adhesion.
Increasing evidence suggests that alcohols act within specific binding pockets of selective neural 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 immunoglobulin cell adhesion molecule L1. An abrupt cutoff exists after 1-butanol, with 1-pentanol and higher 1-alcohols showing no effect. Here, we demonstrate surprisingly strict structural requirements for alcohol inhibition of cell-cell adhesion in L1-transfected NIH 3T3 fibroblasts and in NG108-15 neuroblastoma x glioma hybrid cells treated with BMP-7, an inducer of L1 and neural cell adhesion molecule. The target site discriminates the tertiary structure of straight-chain and branched-chain alcohols and appears to comprise both a hydrophobic binding site and an adjacent hydrophilic allosteric site. Modifications to the 2- and 3-carbon positions of 1-butanol increased potency, whereas modifications that restrict movement about the 4-carbon abolished activity. The effects of ethanol and 1-butanol on cell-cell adhesion were antagonized by 1-pentanol (IC(50) = 715 microM) and 1-octanol (IC(50) = 3.6 microM). 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 injury of the nervous system.
Wilkemeyer
M F
MF
Neurology Service, Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
Sebastian
A B
AB
Smith
S A
SA
Charness
M E
ME
D016475:3T3 Cells; D000438:Alcohols / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta
D000438:Alcohols; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta