A-186253, a specific antagonist of the alpha 4 beta 2 nAChRs: its properties and potential to study brain nicotinic acetylcholine receptors

Neuropharmacology
Valérie ItierGerrit Westera

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 displacemen...Continue Reading

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Citations

Jun 28, 2005·The European Journal of Neuroscience·Marzia LecchiDaniel Bertrand
Jun 26, 2009·Journal of the American Chemical Society·Xiaoqin HuangChang-Guo Zhan
Jul 22, 2005·Journal of Medicinal Chemistry·Anders A JensenPovl Krogsgaard-Larsen

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