| Summary: | In this work, we evaluated the conformational effect promoted by the isosteric exchange of sulfur by selenium in the heteroaromatic ring of new <i>N</i>-acylhydrazone (NAH) derivatives (<b>3</b>–<b>8</b>, <b>13</b>, <b>14</b>), analogues of the cardioactive compounds LASSBio-294 (<b>1</b>) and LASSBio-785 (<b>2</b>). NMR spectra analysis demonstrated a chemical shift variation of the iminic C<i>sp</i><sup>2</sup> 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<sub>2A</sub> receptor (A<sub>2A</sub>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 (<b>1</b>–<b>8</b>). However, the <i>N</i>-methylated compounds (<b>2</b>, <b>6</b>–<b>8</b>) presented a weak partial agonist profile at A<sub>2A</sub>R, contrary to the non-methylated counterparts (<b>1</b>, <b>3</b>–<b>5</b>), which appeared as weak inverse agonists. Additionally, retroisosterism between aromatic rings of NAH on S/Se-isosters mimicked the effect of the <i>N</i>-methylation on intrinsic efficacy at A<sub>2A</sub>R, while <i>meta</i>-substitution in the phenyl ring of the acyl moiety did not. This study showed that the conformational effect of NAH-<i>N</i>-methylation and aromatic rings retroisosterism changed the intrinsic efficacy on A<sub>2A</sub>R, indicating the S/Se-chalcogen effect to drive the conformational behavior of this series of NAH.
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