Inhibition of nitric oxide synthase by straight chain and cyclic alcohols

Nitric oxide appears to mediate some of the central effects of alcohols. However, the direct effects of alcohols on brain nitric oxide synthase have not been determined. In the present study, we tested on purified nitric oxide synthase from rat brain n-alkan-1-ols, n-alkan-2-ol enantiomers, cycloalkanols, and cycloalkanemethanols. In general, the alcohols inhibited nitric oxide synthase activity noncompetitively. Enzyme inhibitory potencies increased with increasing lipophilicity (increasing carbon number) up to the point of 'cutoff', which was C7 for n-alkan-1-ols and C13 for cycloalkanemethanols, indicating that the alcohol binding site on nitric oxide synthase accommodates a maximum chain length of 6-7 carbon atoms. Before the point of 'cutoff', Ki values for the cyclic alcohols and short chain n-alkanols on nitric oxide synthase were less than their respective anesthetic EC50 values. As reported for tadpole anesthesia, there was no stereoselectivity between enantiomeric pairs of secondary alcohols for inhibition of nitric oxide synthase. These results indicate that the nitric oxide synthase inhibitory potency of alcohols of diverse structure is directly related to lipophilicity and length of the alcohols and that direct inhibition of nitric oxide synthase mediates some of the effects of alcohols even at subanesthetic concentrations.