Conformational studies of vasopressin analogues modified with N-methylphenylalanine enantiomers in dimethyl sulfoxide solution.
The conformations of [Arg8]vasopressin (AVP) analogues substituted at positions 2 and 3 with N-methylphenylalanine (MePhe) enantiomers were earlier investigated by using nuclear magnetic resonance (NMR) spectroscopy in aqueous solution. A comparison of the results obtained in H2O/D2O (9:1) and DMSO-d6 has shown the structures in the first solution to be more flexible than those in DMSO-d6. This is manifested by a higher percentage of minor conformations in H2O/D2O. The largest differences between the NMR spectra in both solvents were noticed for [MePhe2, D-MePhe3]AVP (II) and [D-Cys1,MePhe2,D-MePhe3]AVP (III). Namely, in the ROESY spectra in aqueous solution, the cis/trans isomerization between MePhe2-DMePhe3 and D-Cys1-MePhe2 for II and III, respectively, is observed, while in DMSO-d6, the appropriate cross peaks indicate isomerization across the Cys6-Pro7 peptide bond. In the case of the remaining peptides, the position of cis/trans isomerization is the same in aqueous solution and in dimethyl sulfoxide. [D-MePhe2,MePhe3]AVP (V) displays low antiuterotonic and antipressor activities, while [D-MePhe2,)]AVP (IV) is a weak but selective blocker of oxytocin (OT) receptors in the uterus. The former shows similar conformational preferences as another antagonist of V1a and OT receptors-namely, [Acc2,D-Arg8]VP (Acc: 1-aminocyclohexane-1-carboxylic acid)-investigated by us. In the case of IV, the cis peptide bond between residues at positions 2 and 3 might be the reason for selectivity.
Department of Chemistry, University of Gdańsk, Sobieskiego 18, 80-952 Gdańsk, Poland. milka@chem.univ.gda.pl
Emilia
E
Sikorska
Magdalena J
MJ
Slusarz
Bernard
B
Lammek
D000595:Amino Acid Sequence; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism; D004121:Dimethyl Sulfoxide; D066298:In Vitro Techniques; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D011487:Protein Conformation; D012996:Solutions; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001704:Biopolymers; D012996:Solutions; D001127:Arginine Vasopressin; D010649:Phenylalanine; D004121:Dimethyl Sulfoxide