Influence of enantiomers of 1-naphthylalanine in position 2 of VAVP and dVAVP on their pharmacological properties

摘要

The most straightforward approach for peptide modification is to introduce changes into the side chains of chosen amino acids.This strategy allows,among others,by the incorporation of nonproteinogenic amino acid residues,to introduce bulky groups with the aim being to restrict the conformational flexibility of a peptide.Conformational restrictions are of particular value for peptide design targeted towards an increase of receptor selectivity,metabolic stability and the development of highly potent agonists and antagonists.Also,in our laboratory we have shown that such an approach could result in analogues with very interesting pharmacological properties.Previously we reported that the hindering effect caused by the bulky naphthyl moiety of L-1-naphthylalanine(L-1-Nal)or D-1-naphthylalanine(D-l-Nal)in position 2 of arginine vasopressin(AVP)or deamino arginine vasopressin(dAVP),had a significant impact on bioactive conformations of molecules and thus influenced their interaction with V_(1a),V_2 and oxytocic receptors.As a continuation of our efforts to better understand the role of Tyr2,we have now designed,synthesized and determined some pharmacological properties of two new peptides modified in positions 2 and 4 with L-l-Nal or D-l-Nal and valine respectively.In the further two compounds we combined the above substitutions with placement into position 1 of 3-mercaptopropionic acid residue(Mpa).