Influence of bulky 3,3'-diphenylalanine enantiomers replacing position 2 of AVP analogues on their conformations: NMR and molecular modeling studies.
In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3'-diphenylalanine (Dpa) enantiomers: [Mpa(1),Dpa(2),Val(4),D-Arg(8)]VP (I), [Mpa(1),D-Dpa(2),Val(4),D-Arg(8)]VP (II), [D-Dpa(2),D-Arg(8)]VP (III) and [Mpa(1),D-Dpa(2)]AVP (IV). All the peptides exhibit a strong and prolonged antidiuretic activity. Additionally, analogues II, III and IV display antiuterotonic activity and analogue II is also a weak V(1a) receptor blocker. The conformational analysis has shown that beta-turns at positions 2,3 and/or 3,4 are characteristic of OT antagonists. In turn, the beta-turn in the Cys(6)-Gly(9) fragment seems to be crucial for enhancement of the antidiuretic activity. The high accessibility of aromatic side chains at positions 2 and 3 plays a crucial role in antagonist-receptor binding. Moreover, orientation of the Phe(3) side chain is claimed to be important for V(1a) receptor affinity.
Sikorska
Emilia
E
Faculty of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland. milka@chem.univ.gda.pl
Kwiatkowska
Anna
A
Sobolewski
Dariusz
D
Slusarz
Rafał
R
Slusarz
Magdalena J
MJ
D000595:Amino Acid Sequence; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013237:Stereoisomerism
D001127:Arginine Vasopressin; D010649:Phenylalanine; C087556:3,3-diphenylalanine