1. Arginine vasopressin and its analogues--the influence of position 2 modification with 3,3-diphenylalanine enantiomers. Highly potent V2 agonists
Anna Kwiatkowska, Dariusz Sobolewski, Adam Prahl, Lenka Borovicková, Jirina Slaninová, Bernard Lammek Eur J Med Chem. 2009 Jul;44(7):2862-67. doi: 10.1016/j.ejmech.2008.12.010.
Eleven new analogues of arginine vasopressin (AVP) modified in position 2 by 3,3-diphenyl-L-alanine or its D-enantiomer (Dip or D-Dip) were synthesized and pharmacologically evaluated for their pressor, antidiuretic and in vitro uterotonic activities. Both the Dip and D-Dip modifications at position 2 of AVP are sufficient to completely change the pharmacological profile of the peptides. They preserve or increase antidiuretic activity, cause its prolongation, transform uterotonic property in antagonistic one and cancel the effect on blood pressure. Four of the new peptides ([Mpa1,D-Dip2]AVP, [Mpa1,D-Dip2,Val4]AVP, [Mpa1,D-Dip2,D-Arg8]VP, [Mpa1,D-Dip2,Val4,D-Arg8]VP) are exceptionally potent antidiuretic agents with significantly prolonged activities.
2. Analogues of neurohypophyseal hormones, oxytocin and arginine vasopressin, conformationally restricted in the N-terminal part of the molecule
Wioleta Kowalczyk, et al. J Med Chem. 2006 Mar 23;49(6):2016-21. doi: 10.1021/jm058038f.
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 would alter the pharmacological properties of OT, [Mpa1]OT, and [Cpa1]OT (OT=oxytocin; Mpa=3-mercaptopropionic acid; Cpa=1-mercaptocyclohexaneacetic acid) and to investigate how a bulky 3,3-diphenyl-L-alanine residue incorporated in position 2 of AVP, [Mpa1]AVP, and [Cpa1]AVP (AVP=arginine vasopressin) would change the pharmacological profile of the compounds. The next analogues, [Val4]AVP, [Mpa1,Val4]AVP, and [Cpa1,Val4]AVP, had N-benzyl-L-alanine introduced at position 3. The last peptide was designed by Cys1 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.
