Arias, HR, Ortells, MO and Feuerbach, Dominik (2013) Interaction of (-)-reboxetine with nicotinic acetylcholine receptors in different conformational states. International Journal of biochemistry and cell biology.

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  0.49 and 1.92  0.48 M, respectively, (b) binds with ~13-fold higher affinity to the luminal [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. This desensitizing activity is produced in the same concentration range as that for tricyclic antidepressants (TCAs), and (d) interacts with the AChR, where it overlaps the PCP/TCA luminal sites in the resting and desensitized states, but also to non-luminal sites. The non-luminal sites are located at the top of the four transmembrane segments from the Torpedo AChR γ subunit, and whithin the / transmembrane interface on the adult muscle AChR. In conclusion, (-)-reboxetine non-competitively inhibits AChRs by binding to the PCP/TCA luminal site and by inducing receptor desensitization (maybe by interacting with non-luminal sites), a mechanism that is shared by TCAs.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/7743