β-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity

Carrie Haskell-Luevano, Kate Toth, Lakmal Boteju, Constatin Job, Ana Maria De L Castrucci, Mac E. Hadley, Victor J Hruby

Research output: Contribution to journalArticle

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Abstract

Topographically modified melanotropin side chain pharmacophore residues Phe7 and Trp9 in a cyclic peptide template (Ac-Nle4-c[Asp-His-Xaa7-Arg- Yaa9-Lys]-NH2) and Phe7 in a linear peptide template (Ac-Ser-Tyr-Ser- Nle4-Glu-His-Xaa7-Arg-Trp-Giy-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of β- methylphenylalanine (β-MePhe)7 and β-methyltryptophan (β-MeTrp)9 and the two isomers of 1,2,3,4-tetrahydro-β-carboline (Tca)9. Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the β-MePhe7 stereoisomeric peptides; up to a 476-fold difference in potency resulted for the β-MeTrp9 peptides, and about a 50-fold difference between the Tca9-containing peptides. Up to a 40-fold difference in potency resulted for the β-MePhe7 stereoisomeric peptides using the linear template in these assays. The relative potency ranking for modifications 'in the cyclic template of β-MePhe7 were 2R,3S > 2S,3S = 2S,3R > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of β-MeTrp9 were 2R,3S > 2R,3R > 2S,3S >> 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca9 were DTca > LTca in both assays. Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the β-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of β- MeTrp9 stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.

Original languageEnglish (US)
Pages (from-to)2740-2749
Number of pages10
JournalJournal of Medicinal Chemistry
Volume40
Issue number17
DOIs
StatePublished - Aug 15 1997

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Melanocyte-Stimulating Hormones
Methylation
Bioactivity
Lizards
Ligands
Assays
Peptides
Anura
Bioassay
Receptor, Melanocortin, Type 1
Biological Assay
MSH (11-13)
Isomers
Skin
Melanocortin Receptors
Species Specificity
Carbolines
Cyclic Peptides
Stereochemistry
Structure-Activity Relationship

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

β-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity. / Haskell-Luevano, Carrie; Toth, Kate; Boteju, Lakmal; Job, Constatin; Castrucci, Ana Maria De L; Hadley, Mac E.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 40, No. 17, 15.08.1997, p. 2740-2749.

Research output: Contribution to journalArticle

Haskell-Luevano, Carrie ; Toth, Kate ; Boteju, Lakmal ; Job, Constatin ; Castrucci, Ana Maria De L ; Hadley, Mac E. ; Hruby, Victor J. / β-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity. In: Journal of Medicinal Chemistry. 1997 ; Vol. 40, No. 17. pp. 2740-2749.
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abstract = "Topographically modified melanotropin side chain pharmacophore residues Phe7 and Trp9 in a cyclic peptide template (Ac-Nle4-c[Asp-His-Xaa7-Arg- Yaa9-Lys]-NH2) and Phe7 in a linear peptide template (Ac-Ser-Tyr-Ser- Nle4-Glu-His-Xaa7-Arg-Trp-Giy-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of β- methylphenylalanine (β-MePhe)7 and β-methyltryptophan (β-MeTrp)9 and the two isomers of 1,2,3,4-tetrahydro-β-carboline (Tca)9. Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the β-MePhe7 stereoisomeric peptides; up to a 476-fold difference in potency resulted for the β-MeTrp9 peptides, and about a 50-fold difference between the Tca9-containing peptides. Up to a 40-fold difference in potency resulted for the β-MePhe7 stereoisomeric peptides using the linear template in these assays. The relative potency ranking for modifications 'in the cyclic template of β-MePhe7 were 2R,3S > 2S,3S = 2S,3R > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of β-MeTrp9 were 2R,3S > 2R,3R > 2S,3S >> 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca9 were DTca > LTca in both assays. Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the β-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of β- MeTrp9 stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.",
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T1 - β-methylation of the Phe7 and Trp9 melanotropin side chain pharmacophores affects ligand-receptor interactions and prolonged biological activity

AU - Haskell-Luevano, Carrie

AU - Toth, Kate

AU - Boteju, Lakmal

AU - Job, Constatin

AU - Castrucci, Ana Maria De L

AU - Hadley, Mac E.

AU - Hruby, Victor J

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N2 - Topographically modified melanotropin side chain pharmacophore residues Phe7 and Trp9 in a cyclic peptide template (Ac-Nle4-c[Asp-His-Xaa7-Arg- Yaa9-Lys]-NH2) and Phe7 in a linear peptide template (Ac-Ser-Tyr-Ser- Nle4-Glu-His-Xaa7-Arg-Trp-Giy-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of β- methylphenylalanine (β-MePhe)7 and β-methyltryptophan (β-MeTrp)9 and the two isomers of 1,2,3,4-tetrahydro-β-carboline (Tca)9. Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the β-MePhe7 stereoisomeric peptides; up to a 476-fold difference in potency resulted for the β-MeTrp9 peptides, and about a 50-fold difference between the Tca9-containing peptides. Up to a 40-fold difference in potency resulted for the β-MePhe7 stereoisomeric peptides using the linear template in these assays. The relative potency ranking for modifications 'in the cyclic template of β-MePhe7 were 2R,3S > 2S,3S = 2S,3R > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of β-MeTrp9 were 2R,3S > 2R,3R > 2S,3S >> 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca9 were DTca > LTca in both assays. Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the β-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of β- MeTrp9 stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.

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