Influence of Conformationally Constrained Amino Acids Replacing Positions 2 and 3 of Arginine Vasopressin (AVP) and Its Analogues on Their Pharmacological Properties

Synthesis of thirteen new analogues of arginine vasopressin (AVP) has been described. Amino acid residues at positions 2 and 3 of AVP, [3-mercaptopropionic acid (Mpa)1]AVP (dAVP), [Mpa1,D-Arg8]VP (dDAVP) and [Mpa1,Val4,D-Arg8]VP (dVDAVP) were replaced with one amino acid residue using sterically constrained nonproteinogenic amino acids, 4-aminobenzoic acid (Abz), cis-4-aminocyclohexanecarboxylic acid (ach) or its trans-isomer (Ach). In the case of a potent V1a antagonist, [1-mercaptocyclohexaneacetic acid (Cpa)1]AVP, only one similar analogue has been prepared by replacing positions 2 and 3 with Abz. Unfortunately, all new peptides were inactive in bioassays for the pressor, antidiuretic and uterotonic in vitro activities in the rat.