CHARACTERIZATIONS OF THE UNUSUAL DISSOCIATION PROPERTIES OF MELANOTROPIN PEPTIDES FROM THE MELANOCORTIN RECEPTOR, HMC1R

Variation in the degree of prolonged (residual) biological activity of the melanotropin peptides alpha-MSH (alpha-melanocyte-stimulating hor mone, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-G Pro-Val-NH2) and the su perpotent analogues [Nle(4),DPhe(7)]alpha-MSH (MT-I) and [Nle(4),Asp(5 ),DPhe(7),Lys(10)]alpha-MSH(4-10)-NH2 (MT-II) has stimulated considera ble interest regarding this biological phenomena. We have examined the differences in their relative dissociation rates from the melanocorti n receptor, hMC1R, to try and correlate peptide dissociation rates wit h the observations of prolonged biological activity. Interestingly, th ese studies revealed that alpha-MSH remained 25% bound, MT-I 65% bound , and MT-II 86% bound 6 h after the ligand had been removed from the a ssay medium. The relative dissociation rate of MT-II was 4 times slowe r than that for a-MSH and 2 times slower than that for MT-I, which was 2 times slower than that for a-MSH. These data suggest that slow diss ociation kinetics (hours) may contribute to the prolonged biological a ctivities observed for both MT-I and MT-II peptides in vitro and in vi vo. The prolonged binding, biological activities, and enzymatic stabil ity of MT-I and MT-II make them putative candidates for clinical uses such as external scintigraphy for the localization of tumors (i.e., me lanoma).