The cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues

Adriano Mollica, Francesco Pinnen, Azzurra Stefanucci, Federica Feliciani, Cristina Campestre, Luisa Mannina, Anatoly P. Sobolev, Gino Lucente, Peg Davis, Josephine Lai, Shou Wu Ma, Frank Porreca, Victor J Hruby

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH 2) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro 2 represents a crucial factor for the ligand structural and conformational properties. Proline is in fact an efficient stereochemical spacer, capable of inducing favorable spatial orientation of aromatic rings, a key factor for ligand recognition and interaction with receptors. Here the Pro 2 has been replaced by 4(S)-NH 2-2(S)-proline (cAmp), a proline/GABA cis-chimera residue. This bivalent amino acid maintains the capacity to influenc the tetrapeptide conformation and offers the opportunity to generate new linear models and unusually constrained cyclic analogues characterized by an N-terminal Tyr bearing a free α-amino group. The results indicate that the new analogues do not show affinity for both δ and κ opioid receptors and bind only poorly to the μ receptors (for cyclopeptide 9: K i μ = 660 nM; GPI (IC 50) = 1.4% at 1 μM; for linear tetrapeptide acid 13: K i μ = 2000 nM; GPI (IC 50) = 0% at 1 μM; for linear tetrapeptide amide 15: K i μ = 310 nM; GPI (IC 50) = 894 nM).

Original languageEnglish (US)
Pages (from-to)3027-3035
Number of pages9
JournalJournal of Medicinal Chemistry
Volume55
Issue number7
DOIs
StatePublished - Apr 12 2012

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Proline
Opioid Receptors
Ligands
Cyclic Peptides
Amides
gamma-Aminobutyric Acid
Analgesics
Linear Models
Central Nervous System
Amino Acids
Acids
endomorphin 2

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

The cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues. / Mollica, Adriano; Pinnen, Francesco; Stefanucci, Azzurra; Feliciani, Federica; Campestre, Cristina; Mannina, Luisa; Sobolev, Anatoly P.; Lucente, Gino; Davis, Peg; Lai, Josephine; Ma, Shou Wu; Porreca, Frank; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 55, No. 7, 12.04.2012, p. 3027-3035.

Research output: Contribution to journalArticle

Mollica, A, Pinnen, F, Stefanucci, A, Feliciani, F, Campestre, C, Mannina, L, Sobolev, AP, Lucente, G, Davis, P, Lai, J, Ma, SW, Porreca, F & Hruby, VJ 2012, 'The cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues', Journal of Medicinal Chemistry, vol. 55, no. 7, pp. 3027-3035. https://doi.org/10.1021/jm201402v
Mollica, Adriano ; Pinnen, Francesco ; Stefanucci, Azzurra ; Feliciani, Federica ; Campestre, Cristina ; Mannina, Luisa ; Sobolev, Anatoly P. ; Lucente, Gino ; Davis, Peg ; Lai, Josephine ; Ma, Shou Wu ; Porreca, Frank ; Hruby, Victor J. / The cis-4-amino-l-proline residue as a scaffold for the synthesis of cyclic and linear endomorphin-2 analogues. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 7. pp. 3027-3035.
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abstract = "Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH 2) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro 2 represents a crucial factor for the ligand structural and conformational properties. Proline is in fact an efficient stereochemical spacer, capable of inducing favorable spatial orientation of aromatic rings, a key factor for ligand recognition and interaction with receptors. Here the Pro 2 has been replaced by 4(S)-NH 2-2(S)-proline (cAmp), a proline/GABA cis-chimera residue. This bivalent amino acid maintains the capacity to influenc the tetrapeptide conformation and offers the opportunity to generate new linear models and unusually constrained cyclic analogues characterized by an N-terminal Tyr bearing a free {\^I}±-amino group. The results indicate that the new analogues do not show affinity for both δ and κ opioid receptors and bind only poorly to the μ receptors (for cyclopeptide 9: K i μ = 660 nM; GPI (IC 50) = 1.4{\%} at 1 μM; for linear tetrapeptide acid 13: K i μ = 2000 nM; GPI (IC 50) = 0{\%} at 1 μM; for linear tetrapeptide amide 15: K i μ = 310 nM; GPI (IC 50) = 894 nM).",
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AU - Mollica, Adriano

AU - Pinnen, Francesco

AU - Stefanucci, Azzurra

AU - Feliciani, Federica

AU - Campestre, Cristina

AU - Mannina, Luisa

AU - Sobolev, Anatoly P.

AU - Lucente, Gino

AU - Davis, Peg

AU - Lai, Josephine

AU - Ma, Shou Wu

AU - Porreca, Frank

AU - Hruby, Victor J

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AB - Endomorphin-2 (EM-2: Tyr-Pro-Phe-Phe-NH 2) is an endogenous tetrapeptide that combines potency and efficacy with high affinity and selectivity toward the μ opioid receptor, the most responsible for analgesic effects in the central nervous system. The presence of the Pro 2 represents a crucial factor for the ligand structural and conformational properties. Proline is in fact an efficient stereochemical spacer, capable of inducing favorable spatial orientation of aromatic rings, a key factor for ligand recognition and interaction with receptors. Here the Pro 2 has been replaced by 4(S)-NH 2-2(S)-proline (cAmp), a proline/GABA cis-chimera residue. This bivalent amino acid maintains the capacity to influenc the tetrapeptide conformation and offers the opportunity to generate new linear models and unusually constrained cyclic analogues characterized by an N-terminal Tyr bearing a free α-amino group. The results indicate that the new analogues do not show affinity for both δ and κ opioid receptors and bind only poorly to the μ receptors (for cyclopeptide 9: K i μ = 660 nM; GPI (IC 50) = 1.4% at 1 μM; for linear tetrapeptide acid 13: K i μ = 2000 nM; GPI (IC 50) = 0% at 1 μM; for linear tetrapeptide amide 15: K i μ = 310 nM; GPI (IC 50) = 894 nM).

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