Conformational studies of highly potent 1-aminocyclohexane-1-carboxylic acid substituted V2 vasopressin agonists.

Conformational studies of three agonists of V2 receptor modified with 1-aminocyclohexane-1-carboxylic acid (Acc), [Acc2,DArg8]VP, [Acc3]AVP and [Cpa1,Acc3]AVP, using 2D NMR and theoretical calculations are presented in this paper. It is believed that α, α-disubstituted amino acids, such as Acc, affect the formation of either 310 or α-helical conformation. Moreover, a peptide with Acc may adopt either the γ- or an inverse γ-turn over it. Thus, incorporation of Acc into the arginine-vasopressin sequence induced C7-membered ring conformation with Acc at the top of it, and additional formation of β-bend involving residues in the 2–5 fragment of the peptides. Furthermore, the analogues are also characterized by type I of β-turn involving residues Acc3-Cys6 in [Acc3]AVP and [Cpa1,Acc3]AVP, and by type IV or II′ in [Acc2,DArg8]VP. Replacement of Tyr at position 2 of [Acc2,DArg8]VP with Acc afforded a hydrogen bond between the guanidine moiety of DArg8 and the side chain of either Asn5 or Gln4. In the remaining analogues, the β-turn comprising the Cys6-Gly9 residues allows the positively charged side chain of Arg8 to be directed toward Tyr2. The substitution of Cys1 with Cpa1 enhances hydrophobic properties of N-terminal part of the molecule strengthening thereby the affinity to the binding pocket of receptors. [ABSTRACT FROM AUTHOR]