Potent and prolonged acting cyclic lactam analogues of α-melanotropin: Design based on molecular dynamics

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

Research output: Contribution to journalArticle

283 Citations (Scopus)

Abstract

Utilizing results from previous structure-activity relationships and theoretical studies of α-melanotropin (α-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-[Cys4,Cys10]-α-MSH, we have designed a new class of α-MSH4-13 and α-MSH4-10 cyclic lactam fragment analogues of α-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,Xxx5,D-Phe7,Yyy10,Gly 11]-α-MSH4-13-NH2 and Ac-[Nle4,Xxx5,D-Phe7,Yyy 10]-α-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx 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 α-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: α-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys 10]-α-MSH4-10-NH2 (9); Ac-[Nle4,Asp6,D-Phe7,Lys 10]-α-MSH4-10-NH2 (90); Ac-[Nle4,Asp5D-Phe7,Orn 10]-α-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab 10]-α-MSH4-10-NH2 (5); Ac-[Nle4,Asp5,D-Phe7,Dpr 10]-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 α-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 α-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
StatePublished - 1989

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Melanocyte-Stimulating Hormones
Lactams
Molecular Dynamics Simulation
Molecular dynamics
Cyclic Peptides
Biological Assay
Lizards
Bioassay
Melanocytes
Anura
Skin
Rana pipiens
Structure-Activity Relationship
Viperidae
Bioactivity
Pigments
Assays
Theoretical Models

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Potent and prolonged acting cyclic lactam analogues of α-melanotropin : Design based on molecular dynamics. / Al-Obeidi, Fahad; Castrucci, Ana M De L; Hadley, Mac E.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 32, No. 12, 1989, p. 2555-2561.

Research output: Contribution to journalArticle

Al-Obeidi, Fahad ; Castrucci, Ana M De L ; Hadley, Mac E. ; Hruby, Victor J. / Potent and prolonged acting cyclic lactam analogues of α-melanotropin : Design based on molecular dynamics. In: Journal of Medicinal Chemistry. 1989 ; Vol. 32, No. 12. pp. 2555-2561.
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abstract = "Utilizing results from previous structure-activity relationships and theoretical studies of α-melanotropin (α-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-[Cys4,Cys10]-α-MSH, we have designed a new class of α-MSH4-13 and α-MSH4-10 cyclic lactam fragment analogues of α-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,Xxx5,D-Phe7,Yyy10,Gly 11]-α-MSH4-13-NH2 and Ac-[Nle4,Xxx5,D-Phe7,Yyy 10]-α-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx 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 α-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: α-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys 10]-α-MSH4-10-NH2 (9); Ac-[Nle4,Asp6,D-Phe7,Lys 10]-α-MSH4-10-NH2 (90); Ac-[Nle4,Asp5D-Phe7,Orn 10]-α-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab 10]-α-MSH4-10-NH2 (5); Ac-[Nle4,Asp5,D-Phe7,Dpr 10]-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 α-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 α-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.",
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TY - JOUR

T1 - Potent and prolonged acting cyclic lactam analogues of α-melanotropin

T2 - Design based on molecular dynamics

AU - Al-Obeidi, Fahad

AU - Castrucci, Ana M De L

AU - Hadley, Mac E.

AU - Hruby, Victor J

PY - 1989

Y1 - 1989

N2 - Utilizing results from previous structure-activity relationships and theoretical studies of α-melanotropin (α-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-[Cys4,Cys10]-α-MSH, we have designed a new class of α-MSH4-13 and α-MSH4-10 cyclic lactam fragment analogues of α-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,Xxx5,D-Phe7,Yyy10,Gly 11]-α-MSH4-13-NH2 and Ac-[Nle4,Xxx5,D-Phe7,Yyy 10]-α-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx 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 α-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: α-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys 10]-α-MSH4-10-NH2 (9); Ac-[Nle4,Asp6,D-Phe7,Lys 10]-α-MSH4-10-NH2 (90); Ac-[Nle4,Asp5D-Phe7,Orn 10]-α-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab 10]-α-MSH4-10-NH2 (5); Ac-[Nle4,Asp5,D-Phe7,Dpr 10]-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 α-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 α-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.

AB - Utilizing results from previous structure-activity relationships and theoretical studies of α-melanotropin (α-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-[Cys4,Cys10]-α-MSH, we have designed a new class of α-MSH4-13 and α-MSH4-10 cyclic lactam fragment analogues of α-melanotropin. The cyclic peptides have the following general structures: Ac-[Nle4,Xxx5,D-Phe7,Yyy10,Gly 11]-α-MSH4-13-NH2 and Ac-[Nle4,Xxx5,D-Phe7,Yyy 10]-α-MSH4-10-NH2, where Xxx = Glu or Asp and Yyy = Lys, Orn, Dab, or Dpr. Formation of the lactam bridge between the side-chain groups Xxx 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 α-MSH (relative potency = 1), the potencies of the cyclic peptides in the lizard skin bioassay were as follows: α-MSH (1); Ac-[Nle4,Glu5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (6); Ac-[Nle4,Asp5,D-Phe7,Lys10,Gly 11]-α-MSH4-13-NH2 (100); Ac-[Nle4,Glu5,D-Phe7,Lys 10]-α-MSH4-10-NH2 (9); Ac-[Nle4,Asp6,D-Phe7,Lys 10]-α-MSH4-10-NH2 (90); Ac-[Nle4,Asp5D-Phe7,Orn 10]-α-MSH4-10-NH2 (20); Ac-[Nle4,Asp5,D-Phe7,Dab 10]-α-MSH4-10-NH2 (5); Ac-[Nle4,Asp5,D-Phe7,Dpr 10]-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 α-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 α-MSH and its analogues at two different types of pigment cell (melanocyte) receptors.

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