A-186253, a specific antagonist of the alpha 4 beta 2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors.
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.
Itier
Valérie
V
Department of Physiology, Medical Faculty, CMU, University of Geneva, 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland.
Schönbächler
Roland
R
Tribollet
Eliane
E
Honer
Michael
M
Prinz
Katja
K
Marguerat
Anouk
A
Bertrand
Sonia
S
Bunnelle
William H
WH
Schubiger
P August
PA
Meyer
Michael D
MD
Sullivan
James P
JP
Bertrand
Daniel
D
Westera
Gerrit
G
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
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