Theoretical studies, synthesis, and biological activity of 1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4- carbonitrile (C9) as a non-peptide antagonist of the arginine vasopressin V1a and V2 receptors

In this work, the synthesis of 1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5- tetrahydro-1H-1-benzazepine-4-carbonitrile (C9) and the study of its biological activity as a new putative antagonist of vasopressin receptors are described. The chemical identification of the compound C9 was confirmed using ¹H and ¹³C nuclear magnetic resonance. This compound contains a moiety core similar to those of vaptans; therefore, we decided to study the compound's binding on vasopressin receptors (V1aR and V2R), whose models were built, refined by molecular dynamics simulations, and validated through docking studies. The biological effects of C9 on vascular smooth muscle (VSM) contractility and aquaresis were also tested. Rat aortic rings were used to test the inhibitory effect of C9 (0.0, 5.9, 59, and 590 μM) on AVP-induced VSM contraction (10 μM). The inhibition of the antidiuretic effect of vasopressin (50 μU/kg) by C9 (100 μg/kg) was determined using a water load test in rats. The results showed that C9 inhibits aortic rings' contraction in a concentration-dependent manner, whereas C9 exhibited an aquaretic effect on urine flow. Docking studies showed that C9 reaches the vaptan binding site via the V1a and V2 receptors, which explains the similarity in their biological effects. The results indicate that C9 functions as an antagonist on both V1aR and V2R.