CYCLOALKANEMETHANOLS DISCRIMINATE BETWEEN VOLUME-DEPENDENT AND LENGTH-DEPENDENT LOSS OF ACTIVITY OF ALKANOLS AT THE TORPEDO NICOTINIC ACETYLCHOLINE-RECEPTOR

Primary normal alcohols (1-n-alkanols) exert two effects on the nicoti nic acetylcholine receptor when added simultaneously with agonist. Fir st, propanol through decanol inhibit the open channel. Second, methano l through butanol, but not higher homologs, increase the apparent affi nity of the agonist for inducing cation flux. To test the hypothesis t hat the length or volume of the alcohols might account for the fact th at some members of the 1-n-alkanol homologous series lack activity, we have studied in parallel 11 members of another homologous series, i.e ., the cycloalkanemethanols, c(CnH(2n-1))CH2OH. With steadily increasi ng potency, agents from cyclopropanemethanol to cyclodecanemethanol co mpletely inhibited carbachol-stimulated Rb-86+ efflux from nicotinic a cetylcholine receptor-rich postsynaptic vesicles from the electroplaqu es of Torpedo nobiliana, but even 90% saturated solutions of cyclounde canemethanol inhibited only part of the flux and neither cyclododecane methanol nor cyclotetradecanemethanol caused any inhibition. Compariso n of these results with those previously obtained for 1-n-alkanols ind icates that as both series are ascended the cut-off in the inhibitory action on the channel occurs when the volume of the compounds exceeds approximately 340 angstrom3. The apparent affinity for carbachol-induc ed flux was enhanced only by cyclopropanemethanol through cyclooctanem ethanol, consistent with the hypothesis that a critical length of appr oximately 6.3 angstrom cannot be exceeded. Thus, the sites mediating t he two effects have different steric requirements and may be physicall y distinct.