Effect of S-Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel -acylhydrazone Derivatives at the Adenosine A Receptor.

In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new -acylhydrazone (NAH) derivatives (-, , ), analogues of the cardioactive compounds LASSBio-294 () and LASSBio-785 (). NMR spectra analysis demonstrated a chemical shift variation of the iminic C 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 A receptor (AR), 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 (-). However, the -methylated compounds (, -) presented a weak partial agonist profile at AR, contrary to the non-methylated counterparts (, -), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the -methylation on intrinsic efficacy at AR, while -substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH--methylation and aromatic rings retroisosterism changed the intrinsic efficacy on AR, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.