Arias, Hugo, Rosenberg, Avraham, Targowska-Dudac, Katarzyna, Feuerbach, Dominik, Jozwiak, Krzysztof, Moaddel, Ruin and Wainer, Irving (2010) Comparative Interaction between tricyclic antidepressants and mecamylamine with the human α4β2 nicotinic acetylcholine receptor. The International Journal of Biochemistry.

Abstract

We compared the interaction of tricyclic antidepressants (TCAs) with that for the noncompetitive antagonist mecamylamine with the human (h) α4β2 nicotinic acetylcholine receptor (AChR) in different conformational states. The results established that: (a) [3H]imipramine binds to hα4β2 AChRs with relatively high affinity (Kd = 0.83 ± 0.08 μM), but imipramine does not differentiate between desensitized and resting AChRs, (b) although TCAs inhibit (±)-epibatidine-induced Ca2+ influx in HEK293-hα4β2 cells with potencies that are in the same concentration range as that for mecamylamine, TCAs inhibit [3H]imipramine binding to hα4β2 AChRs with affinities >100-fold higher than that for mecamylamine. This can be explained by our docking results where neutral imipramine and mecamylamine interact with the leucine (position 9’) and valine (position 13’) rings by van der Waals contacts, whereas protonated mecamylamine interacts electrostatically with the outer ring (position 20’), (c) van der Waals interactions are in agreement with the thermodynamic results, indicating that imipramine interacts with the desensitized and resting AChRs by a combination of enthalpic and entropic components. However, the entropic component is more important in the desensitized state, suggesting local conformational changes. Our data indicate that TCAs and mecamylamine efficiently inhibit the ion channel by interacting at different luminal sites.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/1978