NS9283, 3-(3-pyridyl)-5-(3-cyanophenyl)-1,2,4-oxadiazole, is a selective positive allosteric modulator of (α4)3(β2)2 nicotinic acetylcholine receptors (nAChRs). It has good subtype selective therapeutic potential afforded by its specific binding to the unique α4−α4 subunit interface present in the (α4)3(β2)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 α4−α4 subunit interface. In this study, new NS9283 analogues were designed, synthesized, and characterized for their ability to selectively potentiate the ACh activity at heterologous (α4)3(β2)2 nAChRs vs nAChR subtypes (α4)2(β2)3, α5α4β2, and α7. With few exceptions, all the NS9283 analogues exerted positive modulation of the (α4)3(β2)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 α4−α4 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.
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Appiani, RebeccaViscarra, FrancoBiggin, Philip C.Bermudez, Isabel Giraudo, AlessandroPallavicini, MarcoBolch, Cristiano
Department of Biological and Medical Sciences
Year of publication: 2024Date of RADAR deposit: 2024-05-10
“This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience, © 2024 American Chemical Society after peer review and technical editing by the publisher.”