Potent and Prolonged Acting Cyclic Lactam Analogues of a-Melanotropin: Design Based on Molecular Dynamics

Fahad Al-Obeidi, Ana M. de L Castrucci, Mac E. Hadley, Victor J. Hruby

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292 Scopus citations

Abstract

Utilizing results from previous structure-activity relationships and theoretical studies of a-melanotropin (a-MSH, Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and its related superpotent analogues, Ac-[Nle4,D-Phe7]-α-MSH and Ac-[[formula omitted]]-α-MSH, we have designed a new class of a-MSH4_13and a-MSH4_10cyclic lactam fragment analogues of a-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,[formula omitted],Glyn]-α-MSH4.13-NH2and Ac-[Nle4,[formula omitted],Yyy10]-α-MSH4.10-NH2, where = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups and Yyy was performed either in solution or on a solid-phase support. Seven cyclic peptides were prepared and bioassayed for their melanotropic potency by using standard frog (Rana pipiens) and lizard (Anolis carolinensis) skin bioassays. Relative to a-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: a-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly11]-α-MSH4_13-NH2(6); Ac-[Nle4,Asp5j)-Phe7,Lys10,Gly11]-α-MSH4_13-NH2(100);Ac-[Nle4,Glu5,D-Phe7,Lys10]-α-MSH4_10-NH2(9);Ac-[Nle4,Asp5,D-Phe7,Lys10]-α-MSH4-10-NH2(90); Ac-[Nle4,Asp5,D-Phe7,Orn10]-α-MSH4_10-NH2(20); Ac-[Nle4,Asp6,D-Phe7,Dab10]-α-MSH4_10-NH2(5); Ac-r -i [Nle4,Asp5,D-Phe7,Dpr10]-α-MSH4_10-NH2(5). Similar results were obtained in the frog skin bioassay, but the analogues were much less potent. Cyclic melanotropins with 23-membered rings exhibited 100-fold higher melanotropic potency than a-MSH with selectivity for the lizard melanocyte receptors over the frog melanocyte receptors. Increasing or decreasing the ring size of these cyclic melanotropins from 23 diminishes the biological potency of the resulting cyclic peptide. The 23- and 24-membered ring analogues showed prolonged (residual) biological activities in both biological assays, but the smaller ring systems (20,21,22) did not. These results provide new insights into the structural and conformational requirements of a-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.

Original languageEnglish (US)
Pages (from-to)2555-2561
Number of pages7
JournalJournal of Medicinal Chemistry
Volume32
Issue number12
DOIs
StatePublished - Dec 1 1989

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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