The interaction of the agonist
JN403 with the human (h)
alpha7 nicotinic acetylcholine receptor (AChR) was compared to that for the competitive antagonist
methyllycaconitine (MLA). The receptor selectivity of
JN403 was studied on the halpha7, halpha3beta4, and halpha4beta2 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. MLA preincubation inhibits JN403-induced Ca(2+) influx in GH3-halpha7 cells with a potency 160-fold higher than that when MLA is co-injected with
JN403. The most probable explanation, based on our dynamics results, is that MLA (more specifically the 3-methyl-2,5-dioxopyrrole ring and the B-D rings) stabilizes the resting conformational state. The order of receptor specificity for
JN403 is as follows: halpha7 > halpha3beta4 ( approximately 40-fold) > halpha4beta2 ( approximately 500-fold). This specificity is based on a larger number of hydrogen bonds between the
carbamate group (another pharmacophore) of
JN403 and the halpha7 sites, the electrostatic repulsion between the positively charged residues around the halpha3beta4 sites and the cationic center of
JN403, fewer hydrogen bonds for the interaction of
JN403 with the halpha3beta4 AChR, and an unfavorable van der Waals interaction between
JN403 and the alpha4-beta2 interface. The higher receptor specificity for
JN403 could be important for the treatment of alpha7-related disorders, including
dementias,
pain-related ailments, depression, anxiety, and wound healing.