Characterization of [3H]ABT-418: a novel cholinergic channel ligand

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 273; no. 3; pp. 1434 - 1441
• Main Authors: Anderson, D J, Williams, M, Pauly, J R, Raszkiewicz, J L, Campbell, J E, Rotert, G, Surber, B, Thomas, S B, Wasicak, J, Arneric, S P
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.06.1995
• Subjects: Alkaloids - metabolism; Animals; Anti-Anxiety Agents - metabolism; Azocines; Brain - metabolism; In Vitro Techniques; Isoxazoles - metabolism; Male; Pyrrolidines - metabolism; Quinolizines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - metabolism; Tritium
• ISSN: 0022-3565; 1521-0103

ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a potent and selective agonist at neuronal nicotinic acetylcholine receptors (nAChRs) with cognitive enhancing and anxiolytic activities. [3H]ABT-418 was found to bind with high affinity (KD = 2.85 +/- 0.14 nM) to membranes prepared from rat brain. Binding of [3H]ABT-418 was characterized by rapid association (T1/2 = 1.4 +/- 0.3 min) and dissociation (T1/2 = 2.9 +/- 0.4 min) half-times. The pharmacology of [3H]ABT-418 binding was consistent with an interaction with the putative alpha 4 beta 2 nAChR subtype. The nAChR agonists, (-)-nicotine, (-)-cytisine and (+/-)-epibatidine, displayed a high affinity (Ki = 0.8 +/- 0.1, 0.2 +/- 0.1 and 0.05 +/- 0.01 nM, respectively) for [3H]ABT-418 binding sites, whereas among nAChR antagonists examined, only dihydro-beta-erythroidine competed with high affinity (Ki = 32 +/- 1.5 nM). Although autoradiography studies indicate that the binding distribution of [3H]ABT-418 and (-)-[3H]cytisine are largely identical, there are some brain regions including the striatum, olivary pretectal nucleus and the superior colliculus, in which [3H]ABT-418 demonstrates significantly (P < .05) less binding. The data in the present study demonstrate that [3H]ABT-418 binds with high affinity to a population of binding sites in the rat brain that have the pharmacological characteristics of neuronal nAChRs. [3H]ABT-418 may, therefore, serve as a useful radioligand to further probe the observed differences in pharmacological properties between ABT-418 and other nicotinic agonists in vivo.