Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

V. J. Hruby; R. S. Agnes; P. Davis; S. W. Ma; Y. S. Lee; T. W. Vanderah; J. Lai; F. Porreca

doi:10.1016/S0024-3205(03)00390-4

Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

V. J. Hruby, R. S. Agnes, P. Davis, S. W. Ma, Y. S. Lee, T. W. Vanderah, J. Lai, F. Porreca

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Disease states such as neuropathic pain offer special challenges in drug design due to the system changes which accompany these diseases. In this manuscript we provide an example of a new approach to drug design in which we have modified a potent and selective peptide ligand for the CCK-2 receptor to a peptide which has potent agonist binding affinity and bioactivity at delta and mu opioid receptors, and simultaneous antagonist activity at CCK receptors. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH₂ (i.e., RSA 601) which have the designed properties.

Original language	English (US)
Pages (from-to)	699-704
Number of pages	6
Journal	Life Sciences
Volume	73
Issue number	6
DOIs	https://doi.org/10.1016/S0024-3205(03)00390-4
State	Published - Jun 27 2003

Keywords

Cholecystokinin antagonists
Neuropathic pain
Opioid agonists
Peptide drug design

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Pharmacology, Toxicology and Pharmaceutics(all)

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10.1016/S0024-3205(03)00390-4

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title = "Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain",

abstract = "Disease states such as neuropathic pain offer special challenges in drug design due to the system changes which accompany these diseases. In this manuscript we provide an example of a new approach to drug design in which we have modified a potent and selective peptide ligand for the CCK-2 receptor to a peptide which has potent agonist binding affinity and bioactivity at delta and mu opioid receptors, and simultaneous antagonist activity at CCK receptors. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH2 (i.e., RSA 601) which have the designed properties.",

keywords = "Cholecystokinin antagonists, Neuropathic pain, Opioid agonists, Peptide drug design",

author = "Hruby, {V. J.} and Agnes, {R. S.} and P. Davis and Ma, {S. W.} and Lee, {Y. S.} and Vanderah, {T. W.} and J. Lai and F. Porreca",

note = "Funding Information: The support of the National Institute of Drug Abuse, U.S. Public Health Service, is gratefully acknowledged. The opinions expressed in this paper are those of the authors and not necessarily those of the USPHS.",

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AU - Hruby, V. J.

AU - Agnes, R. S.

AU - Davis, P.

AU - Ma, S. W.

AU - Lee, Y. S.

AU - Vanderah, T. W.

AU - Lai, J.

AU - Porreca, F.

N1 - Funding Information: The support of the National Institute of Drug Abuse, U.S. Public Health Service, is gratefully acknowledged. The opinions expressed in this paper are those of the authors and not necessarily those of the USPHS.

PY - 2003/6/27

Y1 - 2003/6/27

N2 - Disease states such as neuropathic pain offer special challenges in drug design due to the system changes which accompany these diseases. In this manuscript we provide an example of a new approach to drug design in which we have modified a potent and selective peptide ligand for the CCK-2 receptor to a peptide which has potent agonist binding affinity and bioactivity at delta and mu opioid receptors, and simultaneous antagonist activity at CCK receptors. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH2 (i.e., RSA 601) which have the designed properties.

AB - Disease states such as neuropathic pain offer special challenges in drug design due to the system changes which accompany these diseases. In this manuscript we provide an example of a new approach to drug design in which we have modified a potent and selective peptide ligand for the CCK-2 receptor to a peptide which has potent agonist binding affinity and bioactivity at delta and mu opioid receptors, and simultaneous antagonist activity at CCK receptors. De novo design based on the concept of overlapping pharmacophores was a central hypothesis of this design, and led to compounds such as H-Tyr-DPhe-Gly-DTrp-NMeNle-Asp-Phe-NH2 (i.e., RSA 601) which have the designed properties.

KW - Cholecystokinin antagonists

KW - Neuropathic pain

KW - Opioid agonists

KW - Peptide drug design

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JO - Life Sciences

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Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

Abstract

Keywords

ASJC Scopus subject areas

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