title: A-186253, a specific antagonist of the alpha 4 beta 2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors.
abstract: Imaging the living brain and the distribution of the ligand gated channels that participate in the neurotransmission is one of the challenges that is hoped to bring new insights for the treatment of neurological diseases. Herein, we probed a new nicotinic derivative, A-186253 as a potential molecule to discriminate with high resolution the different neuronal nicotinic receptor subtypes that are expressed in distinct brain areas. Binding with a high affinity of 440 pM at the major brain alpha4beta2 receptor subtype and presenting an excellent safety margin, properties of the A-186253 were thoroughly evaluated. While autoradiography confirmed its specificity for the alpha4beta2 subtype, functional investigations revealed for short exposures a broader spectrum of action at receptors including the ganglionic alpha3beta4 and the homomeric alpha7 subtypes. Specificity was, however, observed at alpha4beta2 when receptors were exposed for several minutes with low concentration of the A-186253. In view of these promising results, the A-186253 was radiolabeled and tested in positron emission tomography on rats and pigs. Despite the high selectivity observed in vitro, the A-186253 displayed a complex binding profile and little displacement by the agonist cytisine. While the A-186253 can be valuable to discriminate receptor subtypes, improvements of this molecule must be brought for in vivo measurements.
authors.affiliation: Department of Physiology, Medical Faculty, CMU, University of Geneva, 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Itier
authors.forename: Roland
authors.initials: R
authors.lastname: Schönbächler
authors.forename: Eliane
authors.initials: E
authors.lastname: Tribollet
authors.forename: Michael
authors.initials: M
authors.lastname: Honer
authors.forename: Katja
authors.initials: K
authors.lastname: Prinz
authors.forename: Anouk
authors.initials: A
authors.lastname: Marguerat
authors.forename: Sonia
authors.initials: S
authors.lastname: Bertrand
authors.forename: William H
authors.initials: WH
authors.lastname: Bunnelle
authors.forename: P August
authors.initials: PA
authors.lastname: Schubiger
authors.forename: Michael D
authors.initials: MD
authors.lastname: Meyer
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
authors.forename: Gerrit
authors.initials: G
authors.lastname: Westera
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013552:Swine; D014981:Xenopus
chemical_list: C495184:2-chloro-3-(4-chlorophenyl)-5-((S)-1-methylpyrrolidin-2-yl)methoxypyridine; D018733:Nicotinic Antagonists; D011725:Pyridines; D011759:Pyrrolidines; D011760:Pyrrolidinones; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2