Di- and heptavalent nicotinic analogues to interfere with α7 nicotinic acetylcholine receptors

Abstract

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 α7 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 µM). Docking investigations provide guidelines to rationalize these experimental findings.

Keywords: Multivalency; Multivalent nicotinics; Nicotinic acetylcholine receptors.