Synthesis and Characterization of New V_1A Antagonist Compounds: The Separation of Four Atropisomeric Stereoisomers

Abstract

A new class of selective vasopressin receptor 1A (V_1A) antagonists was identified, where "methyl-scan" was performed around the benzene ring of the 5-hydroxy-triazolobenzazepine core. This led to the synthesis of two 10-methyl derivatives, each possessing a chiral axis and a stereogenic center. The four atropisomeric stereoisomers (involving two enantiomer pairs and atropisomeric diastereomers) could be successfully isolated and spectroscopically characterized. According to the <i>in vitro</i> pharmacological profiles of the compounds, the human V_1A receptor has a strong preference toward the isomers having an a<i>R</i> axial chirality, the most active isomer being the a<i>R</i>,5<i>S</i> isomer. Furthermore, the structure-activity relationships obtained for the isomers and for the newly synthesized analogues could be tentatively explained by an <i>in silico</i> study.