RJR-2403: a nicotinic agonist with CNS selectivity I. In vitro characterization.

Increasing evidence for an involvement of nicotinic cholinergic systems in neurodegenerative disorders has stimulated the search for compounds with selectivity for CNS nicotinic ACh receptors (nAChRs). To this end, we have evaluated a number of nicotinic agonists for their ability to 1) bind to and up-regulate high-affinity nAChRs, 2) release [3H]-dopamine or induce 86Rb+ efflux in synaptosomes, 3) activate nAChRs in PC12 cells, 4) activate muscle-type nAChRs in human TE671/RD cells and 5) induce contraction of guinea pig ileum. Our results indicate that (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine (RJR-2403) binds with high affinity to rat brain cortex (Ki = 26 +/- 3 nM). Functional studies show that RJR-2403 is comparable to nicotine in activating rat thalamic synaptosomes (EC50 = 732 +/- 155 nM and Emax = 91 +/- 8% for RJR-2403; EC50 = 591 +/- 120 nM and Emax = 100 +/- 25% for nicotine) but is one-tenth as potent in inducing dopamine release (EC50 = 938 +/- 172 nM and Emax = 82 +/- 5% for RJR-2403; EC50 = 100 +/- 25 nM and Emax = 100 +/- 13% for nicotine). At concentrations up to 1 mM, RJR-2403 does not significantly activate nAChRs in PC12 cells, muscle type nAChRs or muscarinic receptors. Dose-response curves for agonist-induced ileum contraction indicate that RJR-2403 is less than one-tenth as potent as nicotine with greatly reduced efficacy. RJR-2403 does not antagonize nicotine-stimulated muscle or ganglionic nAChR function (IC50 > 1 mM). Chronic exposure of M10 cells to RJR-2403 (10 microM) results in an up-regulation of high-affinity nAChRs phenomenologically similar to that seen with nicotine. These results suggest that RJR-2403 interacts with higher potency at CNS nAChR sub-types than at muscle, ganglionic or enteric nAChRs and has higher selectivity for CNS vs. muscle or ganglionic nAChRs than does nicotine.