Design of a New Class of Superpotent Cyclic α-Melanotropins Based on Quenched Dynamic Simulations

A new hishly potent, receptor-selective and prolonged-acting cyclic lactam analogue of α-melanotropin (α-MSH) has been designed and synthesized. Molecular dynamics simulations and molecular mechanics calculations were used in conjunction with results from previous conformational structure-biological activity studies to design a new class of linear and cyclic α-melanotropin (α-MSH) analogues. Examination of these properties of α-MSH and [Nle⁴,D-Phe⁷] α-MSH led to the design of the potent linear fragment analogue Ac-[Nle⁴,Asp⁵,D-Phe⁷,Lys¹⁰]α-MSH_4-10-NH₂, in which the Gly¹⁰ residue of α-MSH₄-₁₀ was replaced by Lys¹⁰ as the major novel change from previous investigations. This in turn led to the synthesis of the cyclic lactam analogue Ac-[Nle⁴,Asp⁵,D-Phe⁷,Lys¹⁰]α-MSH_4-10-NH₂, which was exceptionally potent in the lizard skin (90 times that of α-MSH) and mammalian melanoma tyrosinase (100 times that of α-MSH) assays and in addition exhibited prolonged biological activity.