Highly potent 1-aminocyclohexane-1-carboxylic acid substituted V_2 agonists of arginine vasopressin

摘要

The synthesis of arginine vasopressin(AVP)in the early nineteen-fifties stimulated not only the fields of synthetic chemistry and peptide endocrinology,but also the structure-activity relationship studies of this hormone,and particularly the search for analogues with both high and specific activities.It is believed that the tyrosine residue in position 2 of AVP is involved in initiating the pressor response to AVP,while phenylalanine in position 3,seems to play a role in recognition of this hormone.As a part of our studies on structure-activity relationships of AVP analogues previously,we replaced the residues in positions 2 or 3 of AVP and some of its agonistic and antagonistic analogues with 1-aminocyclohexane-1-carboxylic acid(Acc).The Ace was chosen to reduce the flexibility of peptides by implanting a sterically constrained residue,thus forcing 'the peptide backbone and side chains to adopt specific orientations.The Acc~3 modification has been found to be deleterious for interaction with all three neurohypopheseal hormone receptors,as judged by 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]VP,turned out to be potent antidiuretic agonists.[Acc~2]AVP exhibited moderate pressor agonistic activity and weak antiuterotonic properties.[Acc~2,D-Arg~8]VP has been found to be a weak antagonist in the pressor and uterotonic tests.Moreover,it was interesting to note that one of the Acc~3 substituted peptides,namely [Cpa~1,Acc~3]AVP,turned out to be a selective V_2 agonist.These,in our opinion very interesting results,prompted us to further investigate the influence of the Acc~2 and Acc~3 modifications on pharmacological properties of agonistic and antagonistic analogues of AVP.