Arias, H, Gu, R, Feuerbach, Dominik and Wei, D (2010) Different Interaction between the Agonist JN403 and the Competitive Antagonist Methyllycaconitine with the Human α7 Nicotinic Acetylcholine Receptor. Biochemistry.

Abstract

The interaction of the agonist JN403 with the human (h) α7 nicotinic acetylcholine receptor (AChR) was compared to that of several ligands including the antagonist methyllycaconitine (MLA). The receptor selectivity of JN403 was studied on the hα7, hα3β4, and hα4β2 AChRs. The results established that the cationic center and the hydrophobic group found in JN430 and MLA are important for the interaction with the AChRs. The importance of the cationic center for the formation of cation-π interactions was apparent when gx-50, gx-52, and open3d-51265, which do not have this cation center, failed to induce Ca2+ influx in GH3-hα7 cells, and to inhibit radioligand binding to the hα7, hα3β4, and hα4β2 AChRs, respectively. Moreover, the receptor specificity for JN403 follows the sequence: hα7 > hα3β4 (~40-fold) > hα4β2 (~500-fold). This specificity is based on a higher number of hydrogen bonds between the carbamate group (another pharmacophore) of JN403 and the hα7 sites and to the electrostatic repulsion between the positively charged residues around the hα3β4 and hα4β2?? sites and the cationic center of JN403. MLA pre-incubation inhibits JN403-induced Ca2+ influx in GH3-hα7 cells with 160-fold higher potency compared to that when MLA is co-injected with JN403, probably because MLA (more specifically the 3-methyl-2,5-dioxopyrrole ring and the B, C, D rings) stabilizes the resting conformational state.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:46
Last Modified:	26 Apr 2016 23:46
URI:	https://oak.novartis.com/id/eprint/2720