期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 27, 期 5, 页码 700-707出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.01.013
关键词
Multivalency; Nicotinic acetylcholine receptors; Multivalent nicotinics
资金
- Conseil Regional des Pays de La Loire (MAGGIC project)
- Centre National de la Recherche Scientifique (CNRS)
- Ministere de l'Enseignement Superieur et de la Recherche in France
In the field of nicotinic acetylcholine receptors (nAChRs), recognized as important therapeutic targets, much effort has been dedicated to the development of nicotinic analogues to agonize or antagonize distinct homo-and heteropentamers nAChR subtypes, selectively. In this work we developed di- and heptavalent nicotinic derivatives based on ethylene glycol (EG) and cyclodextrin cores, respectively. The compounds showed a concentration dependent inhibition of acetylcholine-induced currents on alpha 7 nAChR expressed by Xenopus oocytes. Interesting features were observed with the divalent nicotinic derivatives, acting as antagonists with varied inhibitory concentrations (IC50) in function of the spacer arm length. The best divalent compounds showed a 16-fold lowered IC50 compared to the monovalent reference (12 vs 195 mu M). Docking investigations provide guidelines to rationalize these experimental findings.
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