Effect of S-Se Bioisosteric Exchange on Affinity and Intrinsic Efficacy of Novel N-acylhydrazone Derivatives at the Adenosine A2A Receptor

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 Csp(2) 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(2A) receptor (A(2A)R), 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 A(2A)R, 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 A(2A)R, 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 A(2A)R, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.

Automated summary

The study demonstrates that the isosteric exchange of sulfur by selenium can affect the molecular conformation of N-acylhydrazone derivatives, with Se derivatives having stronger intramolecular chalcogen interaction. N-methylation changes the agonist profile at the adenosine A(2A) receptor, while retroisosterism between aromatic rings mimics the effect of N-methylation on intrinsic efficacy.