A new highly 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,Lys 10]α-MSH4-10-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,Lys 10]α-MSH4-10-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.
|Original language||English (US)|
|Number of pages||4|
|Journal||Journal of the American Chemical Society|
|State||Published - 1989|