Structure–activity relationships for nicotine analogs comparing competition for [3H]nicotine binding and psychotropic potency

The structure–activity relationships were established for nicotine analogs and related agents comparing their competition for [3H]nicotine binding to rat brain membranes, Torpedo membranes, and transfected insect cells with their ability to produce prostration in rats following administration into the rat lateral ventricles. A total of 59 compounds were investigated, consisting of pyridine‐ and pyrrolidine‐substituted analogs of nicotine, other tobacco alkaloids and related molecules, various aminoalkylpyridines, and ring‐shifted analogs of nicotine. Some of the compounds were also evaluated for [3H]nicotine binding to Torpedo electroplax membranes and to Sf9 cells expressing an α4β2 nicotinic cholinergic receptor subtype. Linear regression plots of Ki vs ED50 values for prostration of the various classes of the compounds yielded correlation of determination (R2) of 0.923 for the pyridine‐substituted analogs, 0.725 for the pyrrolidine‐substituted analogs, 0.947 for other tobacco alkaloids and related compounds, and 0.537 for all 59 compounds. An excellent correlation was observed comparing Torpedo Ki values with both prostration ED50 values and rat brain Ki values. Within the pyridine‐substituted series, methyl substiuents in the 6‐position resulted in over three‐fold greater potency compared to nicotine, whereas potency decreased markedly with bulkier alkyl and cycloalkyl substituents. Within the pyrrolidine‐substituted series, methyl groups in the 2′‐position only slightly reduced potency compared to nicotine, whereas 3′‐ and 5′‐addition markedly reduces potency. A linear regression plot of the Ki values of brain vs. those of Sf9 cells expressing the α4β2 nicotinic cholinergic receptor subtype yielded a coefficient of correlation of 0.981; a finding which is consistent with the notion that the α4β2 subtype comprises over 90% of total rat brain receptor. Drug Dev. Res. 45:10–16, 1998. © 1998 Wiley‐Liss, Inc.

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