Analogues of Neurohypophyseal Hormones,Oxytocin and Arginine Vasopressin,Conformationally Restricted in the N-Terminal Part of the Molecule

摘要

It is generally accepted that the conformation of the N-terminal part of neurohypophyseal hormones analogues is important for their pharmacological activity.In this work,we decided to investigate how the substitution of positions 2 and 3 with the ethylene-bridged dipeptide -Phe-Phe would alter the pharmacological properties of OT,[Mpa~1]OT,and [Cpa~1]OT (OT=oxytocin;Mpa=3-mercaptopropionic acid;Cpa=1-mercapto-cyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-L-alanine residue incorporated in position 2 of AVP,[Mpa~1]AVP,and [Cpa~1]AVP (AVP=arginine vasopressin) would change the pharmacological profile of the compounds.The next analogues,[Val~4]AVP,[Mpa~1.Val~4]AVP,and [Cpa~1,Val~4]AVP,had N-benzyl-L-alanine introduced at position 3.The last peptide was designed by Cys~1 substitution in AVP by its sterically restricted bulky counterpart,alpha-hydroxymethylcysteine.All the peptides were tested for their in vitro uterotonic,pressor,and antidiuretic activities in the rat.The results of these assays showed that the reduction of conformational freedom of the N-terminal part of the molecule had a significant impact on pharmacological activities.