[1-deamino-4-cyclohexylalanine] arginine vasopressin:: A potent and specific agonist for vasopressin V1b receptors

To date, there are no vasopressin (VP) agonists that exhibit a high affinity and selectivity for the VP V-1b receptor with respect to the V-1a, V-2, and oxytocin receptors. In this study, we describe the synthesis and pharmacological properties of [1-deamino-4-cyclohexylalanine] arginine vasopressin (d[Cha(4)]AVP). Binding experiments performed on various membrane preparations revealed that d[Cha(4)]AVP exhibits a nanomolar affinity for V-1b receptors from various mammalian species (rat, bovine, human). It exhibits high V-1b/V-1a and V-1b/ oxytocin selectivity for rat, human, and bovine receptors. Furthermore, it exhibits high V-1b/V-2 specificity for both bovine and human vasopressin receptors. Functional studies performed on biological models that naturally express V-1b receptors indicate that d[Cha(4)]AVP is an agonist. Like VP, it stimulated basal and corticotropin-releasing factor-stimulated ACTH secretion and basal catecholamine release from rat anterior pituitary and bovine chromaffin cells, respectively. In vivo experiments performed in rat revealed that d[Cha(4)]AVP was able to stimulate both ACTH and corticosterone secretion and exhibits negligible vasopressor activity. It retains about 30% of the antidiuretic activity of VP. This long-sought selective VPV1b receptor ligand with nanomolar affinity will allow a better understanding of V-1b-mediated VP physiological effects and is a promising new tool for V-1b receptor structure-function studies.