METANICOTINE - A NICOTINIC AGONIST WITH CENTRAL-NERVOUS-SYSTEM SELECTIVITY - IN-VITRO AND IN-VIVO CHARACTERIZATION

A growing body of evidence suggests that disruption of nicotinic choli nergic systems may be an important factor in the etiology of a number of different diseases, ranging from neurodegenerative diseases, such a s Alzheimer's and Parkinson's, to ulcerative colitis. The mechanistic basis for such diverse nicotinic effects is likely to lie in the ever growing number of potential receptor subtypes. Therefore, the developm ent of receptor subtype-selective probes is essential to understand th e emerging complexity of nicotinic cholinergic systems and the mechani sms underlying diseases that may involve these systems. Toward this en d, we have evaluated the nicotinic agonist metanicotine, (E)-N-methyl- 4-(3-pyridinyl)-3-butene-1-amine, using the following in vitro and in vivo methods: 1) receptor binding and up-regulation, 2) neurotransmitt er release and ion flux in synaptosomes/cells, 3) in vivo microdialysi s in rats, 4) reversal of scopolamine-induced amnesia in a step-throug h passive-avoidance paradigm, 5) water maze performance in mice, 6) ra dial-arm maze performance in brain-lesioned rats, 7) changes in heart rate and blood pressure, and 8) physiological depression of body tempe rature, locomotor activity, acoustic startle, and respiration rate. Ou r in vitro results indicate that metanicotine binds with high affinity to the major receptor subtype in brain (alpha 4 beta 2), evokes dopam ine release from striatal synaptosomes and Rb+ efflux from thalamic sy naptosomes, but does not activate ganglionic, muscle, or other periphe ral type nicotinic receptors. These results suggest that metanicotine is selective for alpha 4-containing central nervous system (CNS) nicot inic receptors and has reduced selectivity for peripheral nervous syst em (PNS) receptor subtypes. These conclusions are further supported by in vivo studies with metanicotine showing enhanced cognitive effects and significantly lower peripheral effects. Our in vivo results indica te that metanicotine increases the release of acetylcholine, norepinep hrine, dopamine, and serotonin in cortex an disequal to or better than nicotine on measures of cognitive enhancement. By comparison, metanic otine is significantly less potent than nicotine in increasing heart r ate and blood pressure and in causing physiological depression. These results are consistent with in vitro data indicating metanicotine's CN S receptor selectivity, and they suggest that this ligand may be a sui table tool for probing the relationships that underlie the complex cen tral and peripheral pharmacology of nicotinic cholinergic systems. Fur thermore, metanicotine may be a good lead candidate for developing nic otinic agonists as CNS therapeutics with reduced peripheral side effec ts. (C) 1996 Wiley-Liss, Inc.