Novel 3D pharmacophore of α-MSH/γ-MSH hybrids leads to selective human MC1R and MC3R analogues

Minying Cai, Alexander V. Mayorov, Christopher Cabello, Magda Stankova, Dev Trivedi, Victor J Hruby

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

To further evaluate elements that could contribute to the 3D topographical structure of γ-MSH, we have systematically designed a group of linear γ-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle3, with L- or D-Phe6 or D-Nal(2′)6, and with D-Trp 8 or D-Nal(2′)8. It was found that changing the C-terminal acid in γ-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp8 with D-Nal(2′)8 and Phe6 with D-Phe6 in γ-MSH-NH2 forms a selective antagonist for the hMC3R, whereas, substitution of Phe6 with D-Nal(2′)6 and replacing Trp8 with D-Trp 8 at γ-MSH-NH2 yields a selective partial agonist for the hMC1R. Finally, substitution of His5 with Pro5 and Trp8 with D-Nal(2′)8 in γ-MSH-NH2 leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle3-γ-MSH-NH2, there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand - receptor interaction for γ-MSH analogues that may explain the enhanced binding affinities of the Nle 3-γ-MSH-NH2 analogues. Our results indicate that increasing the hydrophobicity and replacing Phe6 and Trp8 with bulkier aromatic amino acid residues is very important for selectivity of α-MSH/γ-MSH hybrids for hMCRs.

Original languageEnglish (US)
Pages (from-to)1839-1848
Number of pages10
JournalJournal of Medicinal Chemistry
Volume48
Issue number6
DOIs
StatePublished - Mar 24 2005

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Melanocyte-Stimulating Hormones
Substitution reactions
Amides
Melanocortin Receptors
Aromatic Amino Acids
Molecular modeling
Hydrophobic and Hydrophilic Interactions
Hydrophobicity
Bioactivity
Binding Sites
Ligands

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel 3D pharmacophore of α-MSH/γ-MSH hybrids leads to selective human MC1R and MC3R analogues. / Cai, Minying; Mayorov, Alexander V.; Cabello, Christopher; Stankova, Magda; Trivedi, Dev; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 48, No. 6, 24.03.2005, p. 1839-1848.

Research output: Contribution to journalArticle

Cai, Minying ; Mayorov, Alexander V. ; Cabello, Christopher ; Stankova, Magda ; Trivedi, Dev ; Hruby, Victor J. / Novel 3D pharmacophore of α-MSH/γ-MSH hybrids leads to selective human MC1R and MC3R analogues. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 6. pp. 1839-1848.
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abstract = "To further evaluate elements that could contribute to the 3D topographical structure of γ-MSH, we have systematically designed a group of linear γ-MSH analogues and evaluated their biological activities: without a N-terminal acetyl, with and without a C-terminal amide, with Nle3, with L- or D-Phe6 or D-Nal(2′)6, and with D-Trp 8 or D-Nal(2′)8. It was found that changing the C-terminal acid in γ-MSH to an amide and replacing Met with Nle leads to increased binding affinities at all four subtypes of melanocortin receptors (10-100 fold). Substitution of Trp8 with D-Nal(2′)8 and Phe6 with D-Phe6 in γ-MSH-NH2 forms a selective antagonist for the hMC3R, whereas, substitution of Phe6 with D-Nal(2′)6 and replacing Trp8 with D-Trp 8 at γ-MSH-NH2 yields a selective partial agonist for the hMC1R. Finally, substitution of His5 with Pro5 and Trp8 with D-Nal(2′)8 in γ-MSH-NH2 leads to a highly potent and selective agonist for the hMC1R. Molecular modeling showed that, at the C-terminal of Nle3-γ-MSH-NH2, there is a reverse-turn-like structure, suggesting that there might be a secondary binding site involved in ligand - receptor interaction for γ-MSH analogues that may explain the enhanced binding affinities of the Nle 3-γ-MSH-NH2 analogues. Our results indicate that increasing the hydrophobicity and replacing Phe6 and Trp8 with bulkier aromatic amino acid residues is very important for selectivity of α-MSH/γ-MSH hybrids for hMCRs.",
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AU - Mayorov, Alexander V.

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AU - Trivedi, Dev

AU - Hruby, Victor J

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