Abstract

NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (alpha 4)(3)(beta 2)(2) nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique alpha 4-alpha 4 subunit interface present in the (alpha 4)(3)(beta 2)(2) nAChR. However, there is currently a lack of structure activity relationship (SAR) studies aimed at developing a class of congeners endowed with the same profile of activity that can help consolidate the druggability of the alpha 4-alpha 4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (alpha 4)(3)(beta 2)(2) nAChRs vs nAChR subtypes (alpha 4)(2)(beta 2)(3), alpha 5 alpha 4 beta 2, and alpha 7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (alpha 4)(3)(beta 2)(2) nAChR ACh-evoked responses. Above all, those modified at the 3-cyanophenyl moiety by replacement with 3-nitrophenyl (4), 4-cyanophenyl (10), and N-formyl-4-piperidinyl (20) showed the same efficacy as NS9283, although with lower potency. Molecular dynamics simulations of NS9283 and some selected analogues highlighted consistency between potentiation activity and pose of the ligand inside the alpha 4-alpha 4 site with the main interaction being with the complementary (-) side and induction of a significant conformational change of the Trp156 residue in the principal (+) side.