EFFECTS OF SOME NICOTINE METABOLITES AND RELATED COMPOUNDS ON ISOLATED SMOOTH MUSCLE

¹ Department of Pharmacology, Medical College of Virginia, Richmond, Virginia

The actions of a series of compounds structurally related to nicotine were observed on isolated rat duodenal segments and on rabbit duodenal and ileal segments. The observations in general appear to support a conclusion that pyridine, pyrrolidine and N-methylpyrrolidine exert a nicotine-like effect on the preparations. This tentative hypothesis gains support from the demonstration that the action of nicotine and these compounds was similarly affected by hexamethonium, tetraethylammonium, atropine, cocaine, dichloroisoproterenol, phentolamine and bretylium. Three mammalian metabolites of (-)-nicotine, (-)-cotinine, (-)-demethylcotinine and 3-pyridylacetic acid, were examined for effects on isolated intestinal segments. (-)-Cotinine caused a relaxation response at a concentration in Tyrode's solution approaching 2.8 x 10^-8 M. (-)-Demethylcotinine produced similar effects. 3-Pyridylacetic acid produced small stimulatory and inhibitory changes at concentrations in the order of 10^-3 M. The results with the entire series of compounds appear to be consistent with previous observations that degradation or alteration of the carbon skeleton of the pyrrolidine ring of nicotine decreases nicotine-like activity. This general phenomenon, perhaps typified by the decreased activity of (-)-cotinine in comparison with nicotine, appears to extend also to N-methylpyrrolidine. N-Methylpyrrolidine, which has nicotine-like activity on the basis of the criteria employed, loses considerable, if not all, of this activity upon conversion to N-methylpyrrolidone-2.