N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine Enantiomers Interact with Luminal and Non-luminal Domains at the Human α3β4 Nicotinic Acetylcholine Receptor

Abstract

The objective of current study is to characterize the interaction of (S,S)- and (R,R)-N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers with human (h) α3β4 nicotinic acetylcholine receptors (AChRs) in different conformational states by using pharmacological and structural approaches. The pharmacological results established that both enantiomers bind with very low affinity to the [3H]imipramine binding sites at hα3β4 AChRs in the resting and desensitized states (apparent Ki~0.5-0.8 mM). The obtained nH values are lower than unity (~0.5) indicating negative cooperative interactions between imipramine and each enantiomer. Based on these results, we suggest that these interactions are allosteric in nature, and consequently, imipramine and each enantiomer bind to non-overlapping sites. This possibility is supported by molecular docking and dynamics results, indicating that the enantiomers, in the protonated and neutral states, interact with mixed luminal/non-luminal and intersubunit (i.e., non-luminal) domains, both formed between the α3 and β4 transmembrane segments. Based on our finding, we suggest that the previously observed antidepressant-like activity elicited by these enantiomers (Targowska-Duda et al, 2013; Neurosci. Lett. 553, 186-190) may be mediated by a novel negative allosteric modulatory mechanism at the hα3β4 AChR.