Conformational studies of vasopressin analogues modified with N-methylphenylalanine enantiomers in dimethyl sulfoxide solution

The conformations of [Arg(8)]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-d(6) has shown the structures in the first solution to be more flexible than those in DMSO-d(6). 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 [MePhe(2), D-MePhe(3)]AVP (II) and [D-Cys(1), MePhe(2), D-MePhe(3)] AVP (III). Namely, in the ROESY spectra in aqueous solution, the cis/trans isomerization between MePhe(2)-DMePhe(3) and D-Cys(1)-MePhe(2) 2 for II and III, respectively, is observed, while in DMSO-d(6), the appropriate cross peaks indicate isomerization across the Cys(6)-Pro(7) 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-MePhe(2) ,MePhe(3)] AVP (V) displays low antiuterotonic and antipressor activities, while [D-MePhe(2,3)] 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 V-1a and OT receptors-namely, [Acc(2), D-Arg(8)] 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. (c) 2006 Wiley Periodicals, Inc.