Analogues of neurohypophyseal hormones, oxytocin and arginine vasopressin, conformationally restricted in the N-terminal part of the molecule.
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.
Kowalczyk
Wioleta
W
Faculty of Chemistry, University of Gdañsk, Sobieskiego 18, 80-952 Gdañsk, Poland. wiola@chem.univ.gda.pl
Prahl
Adam
A
Derdowska
Izabela
I
Sobolewski
Dariusz
D
Olejnik
Jadwiga
J
Zabrocki
Janusz
J
Borovicková
Lenka
L
Slaninová
Jirina
J
Lammek
Bernard
B
D015097:3-Mercaptopropionic Acid / Q000737:chemistry; D000818:Animals; D050034:Antidiuretic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D008297:Male; D008968:Molecular Conformation; D010121:Oxytocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis / Q000494:pharmacology
D050034:Antidiuretic Agents; D004151:Dipeptides; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; D010121:Oxytocin; D015097:3-Mercaptopropionic Acid