RJR-2403 - A NICOTINIC AGONIST WITH CNS SELECTIVITY .2. IN-VIVO CHARACTERIZATION

We have evaluated the physiological and behavioral effects of the CNS- selective nicotinic agonist (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-am ine (RJR-2403) using a number of different methods, including 1) rever sal of pharmacologically induced amnesia in a step-through passive avo idance paradigm, 2) radial arm maze performance in rats with chemicall y induced brain lesions, 3) changes in HR and blood pressure in rats a nd 4) changes in body temperature, Y-maze activity, acoustic startle r esponse and respiration in mice. Our results indicate that RJR-2403 is equal to or better than nicotine on measures of CNS function and cogn itive enhancement. Specifically, RJR-2403 significantly improved passi ve avoidance retention after scopolamine-induced amnesia and enhanced both working and reference memory in rats with ibotenic acid lesions o f the forebrain cholinergic projection system in an 8-arm radial maze paradigm. By comparison, RJR-2403 was 15 to 30-fold less potent than n icotine in decreasing body temperature, respiration, Y-maze rears and Grosses and acoustic startle response. RJR-2403 also demonstrated grea tly reduced cardiovascular effects. RJR-2403 was approximately 10-fold less potent than nicotine in increasing HR and 20-fold less potent in increasing blood pressure. These results are consistent with in vitro data indicating this compound's high selectivity for CNS nicotinic AC h receptor subtypes relative to peripheral ganglionic and muscle-type nicotinic ACh receptors. Therefore, RJR-2403 may be a valuable tool fo r understanding the central and peripheral pharmacology of nicotinic c holinergic systems as well as a potential lead compound for the develo pment of nicotinic therapeutics to treat neurological diseases where c holinergic neurotransmission has been compromised.