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 (nAChR). 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 relationships (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 dynamic 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.

Selective potentiation of the (α4)3(β2)2 nicotinic acetylcholine receptor response by NS9283 analogues / R. Appiani, F. Viscarra, P. Biggin, I. Bermudez, A. Giraudo, M. Pallavicini, C. Bolchi. - In: ACS CHEMICAL NEUROSCIENCE. - ISSN 1948-7193. - (2024), pp. 1-15. [Epub ahead of print] [10.1021/acschemneuro.3c00797]

Selective potentiation of the (α4)3(β2)2 nicotinic acetylcholine receptor response by NS9283 analogues

R. Appiani
Primo
;
A. Giraudo;M. Pallavicini
Penultimo
;
C. Bolchi
Ultimo
2024

Abstract

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 (nAChR). 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 relationships (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 dynamic 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.
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
2024
21-mar-2024
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1040149
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