N,6-dimethyltricyclo[5.2.1.02,6]decan-2-amine enantiomers interact with the human α4β2 nicotinic acetylcholine receptor at luminal and non-luminal domains

Abstract

served antidepressant activity elicited by N,6-dimethyltricyclo[5.2.1.0 2,6 ] decan-2-amine enantiomers may be produced by a novel negative allosteric modulatory mechanism.

Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes

“…Ca 2+ influx measurements were performed in GH3-hα7, HEK293-hα4β2, HEK293-hα3β4, and TE671-hα1β1γδ cells incubated at 37°C as previously described [17][18][19]. In the particular case of CHO-hα4β4 cells, a density of 5 × 10 4 per well was used.…”

“…To determine receptor selectivity, the effect of varenicline on [ 3 H] MLA (4.1 nM) binding to hα7 nAChRs, on [ 3 H]epibatidine (4.6 nM) binding to hα3β4 nAChRs, and on [ 3 H]cytisine (9.1 nM) binding to hα4β2, hα4β4, and Torpedo nAChRs, respectively, was studied as previously described [19][20][21][22]. To determine whether varenicline interacts with the Torpedo and hα4β2 nAChR ion channels, additional studies were conducted using [ 3 H]TCP (20 nM) [21] and [ 3 H]imipramine (13 nM) [23].…”

“…To determine whether varenicline interacts with the Torpedo and hα4β2 nAChR ion channels, additional studies were conducted using [ 3 H]TCP (20 nM) [21] and [ 3 H]imipramine (13 nM) [23]. The effect of varenicline on [ 3 H]cytisine, in the absence (nAChRs are in the resting but activatable state) and presence of 200 μM proadifen [24], and [ 3 H]TCP binding, in the presence of 1 mM CCh (nAChRs are mainly in the desensitized state), was also determined as previously described [21,23] After incubation (2 h), nAChR-bound radioligand was separated from free radioligand by a filtration assay [19][20][21][22][23]. The concentrationresponse data were curve-fitted by nonlinear least squares analysis using the Prism software (GraphPad Software, San Diego, CA).…”

“…Docking simulations were performed using the same protocol as reported previously [19]. In addition, water molecules were incorporated within the binding pockets.…”

“…The docking space was extended to ensure covering two subunits (i.e., α3/β4, α4/β4, α4/β2, α7/α7, α1/δ, and α1/γ) containing the orthosteric (ORT) site, as well as the extracellular domain (EXD) from each nAChR model for additional allosteric (A) sites. The actual docking simulations were performed using the settings described previously [19,23,38]. The lower energy conformations were selected from each cluster of superposed poses.…”