Influence of 1-aminocyclohexane-1-carboxylic acid in position 2 or 3 of AVP and its analogues on their pharmacological properties

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 Acc(3) modifications of AVP, dAVP, [D-Arg(8)]VP and [Cpa(1)]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 Acc(2) substitution selectively altered the interaction with the receptors. Two of the new analogues, [Acc(2) ]AVP and [Acc(2), D-Arg(8)]AVP, are potent antidiuretic agonists. [Acc(2)]AVP exhibits moderate pressor agonistic activity and weak antiuterotonic properties. [Acc(2), D-Arg(8)]AVP has been found to be a weak antagonist in the pressor and uterotonic tests. Another analogue [Cpa(1), Acc(3) ]AVP - turned out to be a highly selective V-2 agonist. This is an unexpected effect, as its parent peptide, [Cpa(1)]AVP is a very potent V-1a receptor antagonist. This is the first Cpa(1) modification to have resulted in V-2 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 V-2 agonists.