(R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors.

S H Zorn, R S Duman, A Giachetti, R Micheletti, E Giraldo, P Krogsgaard-Larsen, S J Enna

Index: J. Pharmacol. Exp. Ther. 242(1) , 173-8, (1987)

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Abstract

Previous reports have suggested that the ethyl ester of (R)-nipecotic acid ethyl ester [(R)-NAEE] displays cholinomimetic properties in vivo. The present study was undertaken to characterize more fully this action by examining the effects of (R)-NAEE in a number of pharmacological and biochemical tests of cholinergic action. (R)-NAEE was found to produce negative inotropic and chronotropic effects on the guinea pig atria (pD2 = 5.91 and 5.62, respectively), and was capable of stimulating contractions in the guinea pig ileum (pD2 = 5.95) and rat jejunum (pD2 = 5.40) at concentrations similar to bethanechol. Both the cardiac and intestinal effects of (R)-NAEE were reversed by atropine. Moreover, (R)-NAEE competed with N-[3H]methylscopolamine and [3H]pirenzepine for muscarinic binding sites in a variety of tissues. Like carbachol, (R)-NAEE inhibited GTP-stimulated adenylate cyclase in rat striatal membranes (EC50 = 52 microM), whereas, unlike carbachol, (R)-NAEE was unable to stimulate inositol phosphate accumulation in rat cerebral cortical slices, behaving as an antagonist in this latter system (pA2 = 5.0). The results indicate that (R)-NAEE interacts directly with cholinergic muscarinic receptors, being an agonist for the M2 subtype and an antagonist at M1 sites.