Structure--function studies of vasopressin analogues with D-3 pyridyl-alanine in position 2.

A number of analogues of vasopressin, incorporating the substitution of D-3'-(pyridyl)-alanine in position 2, were synthesized and tested for antidiuretic (V2), vasoconstrictor (V1a) and ACTH secretory (V1b; pituitary) activities. One analogue, deamino-[D-3'-(pyridyl)-alanine2]arginine-vasopressin (abbreviated d[D-3Pal]VP) was a potent pituitary agonist, weaker antidiuretic agonist, and weak vasoconstrictor antagonist. Another analogue, [D-3'-(pyridyl)-alanine2]arginine-vasopressin, had very weak pituitary activity but no measurable antidiuretic or vasoconstrictor activity. Other D-3'-(pyridyl)-alanine-substituted analogues had only very weak activity in one or two of the bioassays. In further examination of the relationship between the actions of vasopressin on generation of cyclic AMP and secretion of ACTH in pituitary cells, the cyclic AMP responses to d[D-3Pal]VP, to another analogue of vasopressin ([Val4,D-Arg8]VP) with potent agonist activity at pituitary and renal (V2) receptors, and to CRF were compared to that of vasopressin. At the prescribed concentrations, the ACTH secretory responses to vasopressin, d[D-3Pal]VP, and [Val4,D-Arg8]VP were comparable; but only ([Val4,D-Arg8]VP) and CRF, which did not change ACTH secretion, increased intracellular cyclic AMP. These results indicate the possibility of synthesizing analogues of vasopressin with selective activity for the pituitary response and the potential for further study of vasopressin receptor subtypes, using the D-3'-(pyridyl)-alanine substitution. They are also consistent with the concept that the ACTH secretory response to vasopressin by itself is not linked to cyclic AMP, although adenylate cyclase may be activated.