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

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.