POTENTIAL TREATMENT OF ALZHEIMER-DISEASE USING CHOLINERGIC CHANNEL ACTIVATORS (CHCAS) WITH COGNITIVE ENHANCEMENT, ANXIOLYTIC-LIKE, AND CYTOPROTECTIVE PROPERTIES

Compounds that activate neuronal nicotinic acetylcholine receptors (nA ChRs) may have potential benefit in the treatment of dementia, especia lly Alzheimer disease (AD). This article summarizes the preclinical ph armacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxaz ole], a novel analog of(-)-nicotine that is being clinically evaluated for the treatment of AD. ABT-418 is a cholinergic channel activator ( ChCA) with cognitive enhancement and anxiolytic-like activity possessi ng a substantially reduced side-effect profile compared to (-)-nicotin e [Arneric SP, Sullivan JP, Briggs CA, et al. (S)-3-Methyl-5-(1-Methyl -2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with c ognition enhancing and anxiolytic activity. I. In vitro activity. J Ph armacol Exp Ther 1994;270:310-318; Decker MW, Brioni JD, Sullivan JP, et al. (S)-3-Methyl-5-(1-Methyl-2-Pyrrolidiny)Isoxazole (ABT-418): A n ovel cholinergic ligand with cognition-enhancing and anxiolytic activi ties: II. In vivo characterization. J Pharmacol Exp Ther 1994a;270:319 -328; Decker MW, Curzon P, Brioni JD, Arneric SP. Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesion ed rats. fur J Pharmacol 1994;261:217-222; Garvey DS, Wasicak JT, Deck er MW, et al. Novel isoxazoles which interact with brain cholinergic c hannel receptors have intrinsic cognitive enhancing and anxiolytic act ivities. J Med Chem 1994;37:1055-1059]. ABT-418 may be the first agoni st of nAChRs to be developed and evaluated specifically for the treatm ent of AD. Some brief speculation will be given on the potential benef its that this or other ChCAs may have in treating neurodegenerative di sorders as compared with (-)-nicotine, and how this differs from other potential treatment approaches.