Feuerbach, Dominik, Arias, Hugo and Ortells, Marcello (2013) (-)-Reboxetine inhibits muscle nicotinic acetylcholine receptors by interacting with luminal and non-luminal sites. Neurochemistry International.

Abstract

The interaction of (-)-reboxetine, a non-tricyclic norepinephrine selective reuptake inhibitor, with muscle-type nicotinic acetylcholine receptors (AChRs) in different conformational states was studied by functional and structural approaches. The results established that (-)-reboxetine: (a) inhibits (±)-epibatidine-induced Ca2+ influx in human (h) muscle embryonic (hα1β1γδ) and adult (hα1β1εδ) AChRs in a non-competitive manner and with potencies IC50 = 3.86 µM 0.49 and 1.92 µM 0.48 µM, respectively, (b) binds with ~13-fold higher affinity to the [3H]TCP site when the Torpedo AChR is in the desensitized state compared to the resting state, (c) enhances [3H]cytisine binding to the resting but activatable Torpedo AChR but not to the desensitized AChR, suggesting desensitizing properties, (d) overlaps the PCP luminal site located between rings 6’ and 13’ in the Torpedo but not human muscle AChRs. In silico mutation results indicate that ring 9´ is the minimum structural component for (-)-reboxetine binding, and (e) interacts to non-luminal sites located within the transmembrane segments from the Torpedo AChR γ subunit, and at the transmembrane interface from the adult muscle AChR. In conclusion, (-)-reboxetine non-competitively inhibits muscle AChRs by binding to the TPC luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by tricyclic antidepressants.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/10076