Design, synthesis, and biological activities of a potent and selective α-melanotropin antagonist

Publisher Website
Google Scholar
Abstract
Based on structure-activity relationships of the potent α-MSH agonist, Ac-Nle4-Asp5-His6-d-Phe7-Arg8-Trp9-Lys10-NH2, several analogs of the general formula Ac-Nle4-Asp5-Waa6-Xaa7-Yaa8-Zaa9-Lys10-NH2 were synthesized and tested on frog and lizard skin bioassays for their possible inhibitory actions against α-MSH on melanocyte stimulation. When Waa6= Trp, Xaa7= D-Phe, Yaa8= Nle and Zaa = Trp, a highly potent α-MSH antagonist, Ac-Nle-Asp-Trp-d-Phe-Nle-Trp-Lys-NH., with selectivity on the frog skin α-MSH receptor system (PA2= 8.4) was obtained. However, several modifications in the amino acid sequence of the peptide resulted in a complete loss of antagonistic activity and a recovery of very weak agonistic action. The following changes in the amino acid sequence of the peptide were examined; His or d-Trp for Waa, l-Phe for Xaa, Arg, Ala or Pro for Yaa, and d-TV for Zaa. All resulted in full agonists with no antagonistic activity. In addition, lactam cyclization between the Asp5 and Lys10 side chains in the antagonist gave a full agonist and a complete loss of antagonistic activity. Efforts to develop a rational approach for the design of selective α-MSH antagonists for the frog skin α-MSH receptor will be discussed.

This publication has 12 references indexed in Scilit: