Studies Leading to the Identification of the Minimum Active Sequence of aMSH

Early SAR studies with a-MSH were aimed at elucidating the residues in the tridecapeptide that were most responsible for its biological activity. Although previous reviews (140) have covered the results of these studies, it is worthwhile to point out some of the salient features.

1. Replacing Met4 by norleucine (Nle4) increases the potency of the resulting mela-notropin, probably because of the chemically inert and hydrophobic side chain cf' Nle. Early studies had shown that Met is easily oxidized to its sulfone, which increased the hydrophilicity dramatically and thus decreased the bioactivity of the corresponding derivative in the amphibian skin assays.

2. The substitution of Phe7 by D-Phe7 increased the biopotency of the resulting analog, suggesting that a reverse j3-turn conformation (141), formed in the active core sequence (His-Phe-Arg-Trp) of a-MSH, may be important in binding and activity. Consequently, Hruby et al. developed the first highly potent and stable analog cf a-MSH, [Nle4,D-Phe7]-«-MSH [NDP-MSH, MT-I, (Ac-Ser-Tyr-Ser-Nle4-Glu-His-d-Phe7 -Arg-Trp- Gly- Lys- Pro-Val -NH2) ] (141). This compound was found to be a potent agonist of the MCI receptor in amphibian and lizard skin assays.

To further improve the biological efficacy of a-MSH analogs, and to test the p-turn hypothesis, a series of cyclic compounds with greater conformational rigidity compared to that of the linear analog were synthesized. The firstgeneration cyclic analogs replaced the Met4 and Gly10 residues with a pseudoisosteric Cys + Cys residues, to give c[Cys4,Cys10]-a-MSH

(142). This compound was found to be more potent than a-MSH, but lacked prolonged biological potency. In view of the importance of melanotropic peptides in treatment of pig-disorders and as a tool to detect melanoma cancer, quenched dynamic simulation studies (143) were undertaken to develop a-MSH analogs with superpotent and prolonged biological activity in the lizard skin and tyrosinase assay. The key observations (143) from these studies were the following: (1)both a-MSH and NDP-a-MSH assumed folded conformations with a probable /3-turn-like structure at residues seven and eight; (2)the hydrophobic side-chains of His6, d- or l-Phe7, and Trp occupied one face of the folded molecule with the charged (hydrophilic) side-chains of Glu5, Arg3, and Lys11 segregated toward the opposite face of the molecule; (3) although Glu5 and Lys11 occupied the same face, their oppositely charged side-chains were not in proximity for strong coulombic interaction. The molecular mechanic studies also indicated that if Lys11 was moved to replace Gly10, the side-chain of Lys10 could be involved in a strong electrostatic interaction with the side-chain of Glu5, and such an interaction may further stabilize the folded conformation and thus improve binding. These observations led to the development of Ac[Nle4,d-Phe7,Lys10]-a-MSH and Ac[Nle4,Asp5,d-Phe7,Lys10]-a-MSH analogs, which both assumed folded conformations with Asp5 (Glu5) and Lys10 side-chains in proximity to each other when tested

Figure 2.6. Structure of the potent nonselective human melanocortin receptor agonist MT-

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