Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val)

Wayne L. Cody, Brian C. Wilkes, Brian J. Muska, Victor J Hruby, Ana Maria De L Castrucci, Mac E. Hadley

Research output: Contribution to journalArticle

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Abstract

In previous work we reported that [Cys4,Cys10]-α-MSH (II) and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 (III) were superpotent melanotropins. 2,3 Ac-[Cys4,Cys10]-α-MSH4-10-NH2 (VI), which constitutes the cyclic analogue of the putative active site sequence -Met4-Glu5-His6-Phe7-Arg 8-Trp9-Gly10- of α-MSH, was much less active. In the present investigation the contribution of the Lys11 and Pro12 residues of the C-terminal carboxamide tripeptide -Lys11-Pro12-Val13-NH2 to the potency of Cys4,Cys10 containing cyclic melanotropins was studied. Ac-[Cys4,Cys10]-α-MSH4-11-NH2 (V) was less potent than α-MSH in the frog and lizard skin bioassays and the mouse S-91 (Cloudman) melanoma adenylate cyclase assay but more potent than Ac-[Cys4,Cys10]-α-MSH4-10-NH2 in the three assays studied. Ac-[Cys4,Cys10]-α-MSH4-12-NH2 (IV) was considerably more potent than the cyclic 4-11 melanotropin and was, in fact, equipotent or even slightly more potent than [Cys4,Cys10]-α-MSH and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 over the linear portion of the dose-response in all three bioassays. These results demonstrate that Lys11 and Pro12 but to a lesser extent Val13 of the C-terminal tripeptide sequence contributes to the potency of the cyclic melanotropins. The further substitution of a D-Phe7 for the L-Phe7 residue into the cyclic 4-12 analogue resulted in a highly potent compound Ac-[Cys4,D-Phe7,Cys10]-α-MSH 4-12-NH2 (VII) that exhibited highly prolonged biological activity.

Original languageEnglish (US)
Pages (from-to)1186-1190
Number of pages5
JournalJournal of Medicinal Chemistry
Volume27
Issue number9
StatePublished - 1984

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MSH (11-13)
Melanocyte-Stimulating Hormones
Bioassay
Biological Assay
Assays
Lizards
Bioactivity
Adenylyl Cyclases
Anura

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Cody, W. L., Wilkes, B. C., Muska, B. J., Hruby, V. J., Castrucci, A. M. D. L., & Hadley, M. E. (1984). Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val). Journal of Medicinal Chemistry, 27(9), 1186-1190.

Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val). / Cody, Wayne L.; Wilkes, Brian C.; Muska, Brian J.; Hruby, Victor J; Castrucci, Ana Maria De L; Hadley, Mac E.

In: Journal of Medicinal Chemistry, Vol. 27, No. 9, 1984, p. 1186-1190.

Research output: Contribution to journalArticle

Cody, WL, Wilkes, BC, Muska, BJ, Hruby, VJ, Castrucci, AMDL & Hadley, ME 1984, 'Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val)', Journal of Medicinal Chemistry, vol. 27, no. 9, pp. 1186-1190.
Cody WL, Wilkes BC, Muska BJ, Hruby VJ, Castrucci AMDL, Hadley ME. Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val). Journal of Medicinal Chemistry. 1984;27(9):1186-1190.
Cody, Wayne L. ; Wilkes, Brian C. ; Muska, Brian J. ; Hruby, Victor J ; Castrucci, Ana Maria De L ; Hadley, Mac E. / Cyclic melanotropins. 5. Importance of the C-terminal tripeptide (Lys-Pro-Val). In: Journal of Medicinal Chemistry. 1984 ; Vol. 27, No. 9. pp. 1186-1190.
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abstract = "In previous work we reported that [Cys4,Cys10]-α-MSH (II) and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 (III) were superpotent melanotropins. 2,3 Ac-[Cys4,Cys10]-α-MSH4-10-NH2 (VI), which constitutes the cyclic analogue of the putative active site sequence -Met4-Glu5-His6-Phe7-Arg 8-Trp9-Gly10- of α-MSH, was much less active. In the present investigation the contribution of the Lys11 and Pro12 residues of the C-terminal carboxamide tripeptide -Lys11-Pro12-Val13-NH2 to the potency of Cys4,Cys10 containing cyclic melanotropins was studied. Ac-[Cys4,Cys10]-α-MSH4-11-NH2 (V) was less potent than α-MSH in the frog and lizard skin bioassays and the mouse S-91 (Cloudman) melanoma adenylate cyclase assay but more potent than Ac-[Cys4,Cys10]-α-MSH4-10-NH2 in the three assays studied. Ac-[Cys4,Cys10]-α-MSH4-12-NH2 (IV) was considerably more potent than the cyclic 4-11 melanotropin and was, in fact, equipotent or even slightly more potent than [Cys4,Cys10]-α-MSH and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 over the linear portion of the dose-response in all three bioassays. These results demonstrate that Lys11 and Pro12 but to a lesser extent Val13 of the C-terminal tripeptide sequence contributes to the potency of the cyclic melanotropins. The further substitution of a D-Phe7 for the L-Phe7 residue into the cyclic 4-12 analogue resulted in a highly potent compound Ac-[Cys4,D-Phe7,Cys10]-α-MSH 4-12-NH2 (VII) that exhibited highly prolonged biological activity.",
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AU - Cody, Wayne L.

AU - Wilkes, Brian C.

AU - Muska, Brian J.

AU - Hruby, Victor J

AU - Castrucci, Ana Maria De L

AU - Hadley, Mac E.

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AB - In previous work we reported that [Cys4,Cys10]-α-MSH (II) and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 (III) were superpotent melanotropins. 2,3 Ac-[Cys4,Cys10]-α-MSH4-10-NH2 (VI), which constitutes the cyclic analogue of the putative active site sequence -Met4-Glu5-His6-Phe7-Arg 8-Trp9-Gly10- of α-MSH, was much less active. In the present investigation the contribution of the Lys11 and Pro12 residues of the C-terminal carboxamide tripeptide -Lys11-Pro12-Val13-NH2 to the potency of Cys4,Cys10 containing cyclic melanotropins was studied. Ac-[Cys4,Cys10]-α-MSH4-11-NH2 (V) was less potent than α-MSH in the frog and lizard skin bioassays and the mouse S-91 (Cloudman) melanoma adenylate cyclase assay but more potent than Ac-[Cys4,Cys10]-α-MSH4-10-NH2 in the three assays studied. Ac-[Cys4,Cys10]-α-MSH4-12-NH2 (IV) was considerably more potent than the cyclic 4-11 melanotropin and was, in fact, equipotent or even slightly more potent than [Cys4,Cys10]-α-MSH and Ac-[Cys4,Cys10]-α-MSH4-13-NH2 over the linear portion of the dose-response in all three bioassays. These results demonstrate that Lys11 and Pro12 but to a lesser extent Val13 of the C-terminal tripeptide sequence contributes to the potency of the cyclic melanotropins. The further substitution of a D-Phe7 for the L-Phe7 residue into the cyclic 4-12 analogue resulted in a highly potent compound Ac-[Cys4,D-Phe7,Cys10]-α-MSH 4-12-NH2 (VII) that exhibited highly prolonged biological activity.

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