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1.
Molecules ; 26(23)2021 Dec 04.
Artículo en Inglés | MEDLINE | ID: mdl-34885946

RESUMEN

In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new N-acylhydrazone (NAH) derivatives (3-8, 13, 14), analogues of the cardioactive compounds LASSBio-294 (1) and LASSBio-785 (2). NMR spectra analysis demonstrated a chemical shift variation of the iminic Csp2 of NAH S/Se-isosters, suggesting a stronger intramolecular chalcogen interaction for Se-derivatives. To investigate the pharmacological profile of these compounds at the adenosine A2A receptor (A2AR), we performed a previously validated functional binding assay. As expected for bioisosteres, the isosteric-S/Se replacement affected neither the affinity nor the intrinsic efficacy of our NAH derivatives (1-8). However, the N-methylated compounds (2, 6-8) presented a weak partial agonist profile at A2AR, contrary to the non-methylated counterparts (1, 3-5), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the N-methylation on intrinsic efficacy at A2AR, while meta-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-N-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A2AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.


Asunto(s)
Hidrazonas/química , Receptor de Adenosina A2A/metabolismo , Selenio/química , Azufre/química , Tiofenos/química , Agonistas del Receptor de Adenosina A2/química , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Humanos , Hidrazonas/farmacología , Masculino , Modelos Moleculares , Ratas Wistar , Selenio/farmacología , Azufre/farmacología , Tiofenos/farmacología
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