In this study we describe the synthesis and some pharmacological properties of seven new analogues of arginine vasopressin (AVP) substituted in position 2 or 3 with 1-aminocyclohexane-1-carboxylic acid (Acc). All peptides were tested for the pressor, antidiuretic and uterotonic in vitro activities. The Acc3 modifications of AVP, dAVP, [d-Arg8]VP and [Cpa1]AVP have been found to be deleterious for interaction with all three neurohypophyseal hormone receptors, as judged from the several orders of magnitude decreased biological activities, whereas Acc2 substitution selectively altered the interaction with the receptors. Two of the new analogues, [Acc2]AVP and [Acc2, d-Arg8]AVP, are potent antidiuretic agonists. [Acc2]AVP exhibits moderate pressor agonistic activity and weak antiuterotonic properties. [Acc2, d-Arg8]AVP has been found to be a weak antagonist in the pressor and uterotonic tests. Another analogue - [Cpa1, Acc3]AVP - turned out to be a highly selective V2 agonist. This is an unexpected effect, as its parent peptide, [Cpa1]AVP is a very potent V1a receptor antagonist. This is the first Cpa1 modification to have resulted in V2 agonism enhancement. Besides providing useful information about structure-activity relationships, our results could open up new possibilities in the design of highly potent and selective V2 agonists.

The synthesis and some pharmacological properties of two sets of analogues, one consisting of six peptides with 1-aminocyclohexane-1-carboxylic acid (Acc) in position 2 and the other with the amino acid in position 3, have been described. All the peptides were tested for their pressor, antidiuretic, and uterotonic in vitro activities. The Acc(2) modification has been shown to selectively modulate the activities of the analogues. Four of the compounds were highly potent antidiuretic agonists with different pressor and uterotonic activities. On the other hand, the 3-substituted counterparts failed to exhibit any of the activities. One exception was provided by the [Mpa(1),Acc(3),Val(4),D-Arg(8)]VP analogue, which exhibited antidiuretic activity matching that of AVP, yet, unlike AVP, it was fairly selective.

The biological activity of a new synthetic analog of vasopressin, deamino[D-3-(3'-pyridyl)-Ala2, Arg8] vasopressin, was assessed in a number of assays. Antidiuretic (V2) and vasoconstrictor (V1), agonist and antagonist activities were assessed in rats in vivo. Corticotropin-releasing activity was assessed with cultured dissociated ovine anterior pituitary cells in vitro and in sheep in vivo. Compared to vasopressin, the analog is a weak agonist at antidiuretic receptors (1/381 compared to AVP); it is a weak antagonist of the vasoconstrictor response (pA2 = 6.22). Nonetheless, the analog is a full, relatively potent agonist at pituitary corticotrope receptors (relative potency of 1/36). These data indicate that analogs of vasopressin can be synthesized which are relatively selective for agonist activity at pituitary vasopressin receptors, and in doing so, further support the contention that the pituitary receptor is quite distinct from the classical V1 receptor.