Structure-activity relationships of cyclic lactam analogues of α-melanocyte-stimulating hormone (α-MSH) targeting the human melanocortin-3 receptor

Alexander V. Mayorov, Minying Cai, Erin S. Palmer, Matthew M. Dedek, James P. Cain, April R. Van Scoy, Bahar Tan, Josef Vagner, Dev Trivedi, Victor J Hruby

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro6 and the ε-amino group of Lys10 of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro6-D-Phe7/D-Nal(2′)7-Arg 8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]- NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3- pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the D-Phe/D-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D- Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte- stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.

Original languageEnglish (US)
Pages (from-to)187-195
Number of pages9
JournalJournal of Medicinal Chemistry
Volume51
Issue number2
DOIs
StatePublished - Jan 24 2008

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Melanocyte-Stimulating Hormones
Lactams
Carbon Monoxide
Structure-Activity Relationship
Pyrazines
Dicarboxylic Acids
Inhibitory Concentration 50
Receptor, Melanocortin, Type 3
human MC3R protein
Peptides

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-activity relationships of cyclic lactam analogues of α-melanocyte-stimulating hormone (α-MSH) targeting the human melanocortin-3 receptor. / Mayorov, Alexander V.; Cai, Minying; Palmer, Erin S.; Dedek, Matthew M.; Cain, James P.; Van Scoy, April R.; Tan, Bahar; Vagner, Josef; Trivedi, Dev; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 51, No. 2, 24.01.2008, p. 187-195.

Research output: Contribution to journalArticle

Mayorov, Alexander V. ; Cai, Minying ; Palmer, Erin S. ; Dedek, Matthew M. ; Cain, James P. ; Van Scoy, April R. ; Tan, Bahar ; Vagner, Josef ; Trivedi, Dev ; Hruby, Victor J. / Structure-activity relationships of cyclic lactam analogues of α-melanocyte-stimulating hormone (α-MSH) targeting the human melanocortin-3 receptor. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 2. pp. 187-195.
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abstract = "A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro6 and the ε-amino group of Lys10 of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro6-D-Phe7/D-Nal(2′)7-Arg 8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]- NH2, EC50 = 27 nM, 70{\%} max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3- pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the D-Phe/D-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D- Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte- stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.",
author = "Mayorov, {Alexander V.} and Minying Cai and Palmer, {Erin S.} and Dedek, {Matthew M.} and Cain, {James P.} and {Van Scoy}, {April R.} and Bahar Tan and Josef Vagner and Dev Trivedi and Hruby, {Victor J}",
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T1 - Structure-activity relationships of cyclic lactam analogues of α-melanocyte-stimulating hormone (α-MSH) targeting the human melanocortin-3 receptor

AU - Mayorov, Alexander V.

AU - Cai, Minying

AU - Palmer, Erin S.

AU - Dedek, Matthew M.

AU - Cain, James P.

AU - Van Scoy, April R.

AU - Tan, Bahar

AU - Vagner, Josef

AU - Trivedi, Dev

AU - Hruby, Victor J

PY - 2008/1/24

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AB - A variety of dicarboxylic acid linkers introduced between the α-amino group of Pro6 and the ε-amino group of Lys10 of the cyclic lactam α-melanocyte-stimulating hormone (α-MSH)-derived Pro6-D-Phe7/D-Nal(2′)7-Arg 8-Trp9-Lys10-NH2 pentapeptide template lead to nanomolar range and selective hMC3R agonists and antagonists. Replacement of the Pro6 residue and the dicarboxylic acid linker with 2,3-pyrazine-dicarboxylic acid furnished a highly selective nanomolar range hMC3R partial agonist (analogue 12, c[CO-2,3-pyrazine-CO-D-Phe-Arg-Trp-Lys]- NH2, EC50 = 27 nM, 70% max cAMP) and an hMC3R antagonist (analogue 13, c[CO-2,3-pyrazine-CO-D-Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 23 nM). Modeling experiments suggest that 2,3- pyrazinedicarboxylic acid stabilizes a β-turn-like structure with the D-Phe/D-Nal(2′) residues, which explains the high potency of the corresponding peptides. Placement of a Nle residue in position 6 produced a hMC3R/hMC5R antagonist (analogue 15, c[CO-(CH2)2-CO-Nle-D- Nal(2′)-Arg-Trp-Lys]-NH2, IC50 = 12 and 17 nM, respectively), similarly to the previously described cyclic γ-melanocyte- stimulating hormone (γ-MSH)-derived hMC3R/hMC5R antagonists. These newly developed melanotropins will serve as critical biochemical tools for elucidating the full spectrum of functions performed by the physiologically important melanocortin-3 receptor.

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