RJR-2403 - A NICOTINIC AGONIST WITH CNS SELECTIVITY .1. IN-VITRO CHARACTERIZATION

Increasing evidence for an involvement of nicotinic cholinergic system s in neurodegenerative disorders has stimulated the search for compoun ds with selectivity for CNS nicotinic ACh receptors (nAChRs). To this end, we have evaluated a number of nicotinic agonists for their abilit y to 1) bind to and up-regulate high-affinity nAChRs, 2) release [H-3] -dopamine or induce Rb-86(+) efflux in synaptosomes, 3) activate nAChR s in PC12 cells, 4) activate muscle-type nAChRs in human TE671/RD cell s 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 wi th high affinity to rat brain cortex (K-i = 26 +/- 3 nM). Functional s tudies show that RJR-2403 is comparable to nicotine in activating rat thalamic synaptosomes (EC(50) = 732 +/- 155 nM and E(max) = 91 +/- 8% for RJR-2403; EC(50) = 591 +/- 120 nM and E(max) = 100 +/- 25% for nic otine) but is one-tenth as potent in inducing dopamine release (EC(50) = 938 +/- 172 nM and E(max) = 82 +/- 5% for RJR-2403; EC(50) = 100 +/ - 25 nM and E(max) = 100 +/- 13% for nicotine). At concentrations up t o 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-240 3 does not antagonize nicotine-stimulated muscle or ganglionic nAChR f unction (IC50 > 1 mM). Chronic exposure of M10 cells to RJR-2403 (10 m u M) results in an up-regulation of high-affinity nAChRs phenomenologi cally similar to that seen with nicotine. These results suggest that R JR-2403 interacts with higher potency at CNS nAChR subtypes than at mu scle, ganglionic or enteric nAChRs and has higher selectivity for CNS vs. muscle or ganglionic nAChRs than does nicotine.