Structure-activity studies of the melanocortin peptides: Discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors

Paolo Grieco, Antonio Lavecchia, Minying Cai, Devendra Trivedi, David Weinberg, Tanya MacNeil, L. H T Van der Ploeg, Victor J Hruby

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Abstract

We have designed and synthesized several novel cyclic SHU9119 analogues (Ac-Nle4-[Asp5-His6-DNal (2′)7-Arg8-Trp9- Lys10]-NH2) modified in position 6 with nonconventional amino acids. SHU9119 is a high affinity nonselective antagonist at hMC3R and hMC4R with potent agonist activity at hMC1R and hMC5R. We measured the binding affinity and agonist potency of the novel analogues at cloned hMC3R, hMC4R, and hMC5R receptors and identified several selective, high affinity hMC3R and hMC4R antagonists. Compound 4 containing Che substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.48 nM) with 100-fold selectivity over hMC3R antagonist. Analogue 7 with a Cpe substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.51 nM) with a 200-fold selectivity vs the hMC3R. Interestingly, analogue 9 with an Acpc residue in position 6 is a high affinity hMC3R antagonist (IC50 = 2.5 nM) with 100-fold selectivity vs the hMC4R antagonist based on its binding affinities. This compound represents the first cyclic lactam antagonist with high selectivity for the hMC3R vs hMC4R. To understand the possible structural basis responsible for selectivity of these peptides at hMCR3 and hMCR4, we have carried out a molecular modeling study in order to examine the conformational properties of the cyclic peptides modified in position 6 with conformationally restricted amino acids.

Original languageEnglish (US)
Pages (from-to)5287-5294
Number of pages8
JournalJournal of Medicinal Chemistry
Volume45
Issue number24
DOIs
StatePublished - Nov 21 2002

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Melanocortins
Inhibitory Concentration 50
Substitution reactions
Amino Acids
Lactams
Cyclic Peptides
Peptides
Molecular modeling
SHU 9119

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Structure-activity studies of the melanocortin peptides : Discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. / Grieco, Paolo; Lavecchia, Antonio; Cai, Minying; Trivedi, Devendra; Weinberg, David; MacNeil, Tanya; Van der Ploeg, L. H T; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 45, No. 24, 21.11.2002, p. 5287-5294.

Research output: Contribution to journalArticle

Grieco, Paolo ; Lavecchia, Antonio ; Cai, Minying ; Trivedi, Devendra ; Weinberg, David ; MacNeil, Tanya ; Van der Ploeg, L. H T ; Hruby, Victor J. / Structure-activity studies of the melanocortin peptides : Discovery of potent and selective affinity antagonists for the hMC3 and hMC4 receptors. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 24. pp. 5287-5294.
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abstract = "We have designed and synthesized several novel cyclic SHU9119 analogues (Ac-Nle4-[Asp5-His6-DNal (2′)7-Arg8-Trp9- Lys10]-NH2) modified in position 6 with nonconventional amino acids. SHU9119 is a high affinity nonselective antagonist at hMC3R and hMC4R with potent agonist activity at hMC1R and hMC5R. We measured the binding affinity and agonist potency of the novel analogues at cloned hMC3R, hMC4R, and hMC5R receptors and identified several selective, high affinity hMC3R and hMC4R antagonists. Compound 4 containing Che substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.48 nM) with 100-fold selectivity over hMC3R antagonist. Analogue 7 with a Cpe substitution in position 6 is a high affinity hMC4R antagonist (IC50 = 0.51 nM) with a 200-fold selectivity vs the hMC3R. Interestingly, analogue 9 with an Acpc residue in position 6 is a high affinity hMC3R antagonist (IC50 = 2.5 nM) with 100-fold selectivity vs the hMC4R antagonist based on its binding affinities. This compound represents the first cyclic lactam antagonist with high selectivity for the hMC3R vs hMC4R. To understand the possible structural basis responsible for selectivity of these peptides at hMCR3 and hMCR4, we have carried out a molecular modeling study in order to examine the conformational properties of the cyclic peptides modified in position 6 with conformationally restricted amino acids.",
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AU - Trivedi, Devendra

AU - Weinberg, David

AU - MacNeil, Tanya

AU - Van der Ploeg, L. H T

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