title: Characterization of [3H]ABT-418: a novel cholinergic channel ligand.
abstract: 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.
authors.affiliation: Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: J R
authors.initials: JR
authors.lastname: Pauly
authors.forename: J L
authors.initials: JL
authors.lastname: Raszkiewicz
authors.forename: J E
authors.initials: JE
authors.lastname: Campbell
authors.forename: G
authors.initials: G
authors.lastname: Rotert
authors.forename: B
authors.initials: B
authors.lastname: Surber
authors.forename: S B
authors.initials: SB
authors.lastname: Thomas
authors.forename: J
authors.initials: J
authors.lastname: Wasicak
authors.forename: S P
authors.initials: SP
authors.lastname: Arneric
mesh_terms: D000470:Alkaloids / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism*; D001392:Azocines; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000378:metabolism*; D008297:Male; D011759:Pyrrolidines / Q000378:metabolism*; D011807:Quinolizines; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014316:Tritium; D000093843:Quinolizidine Alkaloids
chemical_list: D000470:Alkaloids; D014151:Anti-Anxiety Agents; D001392:Azocines; D007555:Isoxazoles; D011759:Pyrrolidines; D011807:Quinolizines; D011978:Receptors, Nicotinic; D014316:Tritium; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; C004712:cytisine; D000093843:Quinolizidine Alkaloids