Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Richard S. Agnes; Jinfa Ying; Katalin E. Kövér; Yeon Sun Lee; Peg Davis; Shou wu Ma; Hamid Badghisi; Frank Porreca; Josephine Lai; Victor J Hruby

doi:10.1016/j.peptides.2008.03.022

Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Richard S. Agnes, Jinfa Ying, Katalin E. Kövér, Yeon Sun Lee, Peg Davis, Shou wu Ma, Hamid Badghisi, Frank Porreca, Josephine Lai, Victor J Hruby

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

21 Scopus citations

Abstract

Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH₂) showed potent binding and agonist activities at δ and μ opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

Original language	English (US)
Pages (from-to)	1413-1423
Number of pages	11
Journal	Peptides
Volume	29
Issue number	8
DOIs	https://doi.org/10.1016/j.peptides.2008.03.022
State	Published - Aug 2008

Keywords

Bifunctional peptides
G-Protein coupled receptors
Multivalent ligands
NMR conformation
Overlapping pharmacophores
Pain
Tolerance

ASJC Scopus subject areas

Biochemistry
Physiology
Endocrinology
Cellular and Molecular Neuroscience

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10.1016/j.peptides.2008.03.022

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title = "Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors",

abstract = "Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and μ opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.",

keywords = "Bifunctional peptides, G-Protein coupled receptors, Multivalent ligands, NMR conformation, Overlapping pharmacophores, Pain, Tolerance",

author = "Agnes, {Richard S.} and Jinfa Ying and K{\"o}v{\'e}r, {Katalin E.} and Lee, {Yeon Sun} and Peg Davis and Ma, {Shou wu} and Hamid Badghisi and Frank Porreca and Josephine Lai and Hruby, {Victor J}",

note = "Funding Information: This research was supported in part by grants from the USPHS, National Institute on Drug Abuse, DA12394 and DA06284, and from University of Arizona NMR grant (NSF 9729350). K.E.K. was supported by a grant from National Science Foundation and the Hungarian Scientific Research Fund, OTKA NK-68578. The opinions expressed are those of the authors and not necessarily those of NIDA. Authors are thankful to Ms. Margie Colie for her assistance with the manuscript. ",

year = "2008",

month = aug,

doi = "10.1016/j.peptides.2008.03.022",

language = "English (US)",

volume = "29",

pages = "1413--1423",

journal = "Peptides",

issn = "0196-9781",

publisher = "Elsevier Inc.",

number = "8",

}

TY - JOUR

T1 - Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

AU - Agnes, Richard S.

AU - Ying, Jinfa

AU - Kövér, Katalin E.

AU - Lee, Yeon Sun

AU - Davis, Peg

AU - Ma, Shou wu

AU - Badghisi, Hamid

AU - Porreca, Frank

AU - Lai, Josephine

AU - Hruby, Victor J

N1 - Funding Information: This research was supported in part by grants from the USPHS, National Institute on Drug Abuse, DA12394 and DA06284, and from University of Arizona NMR grant (NSF 9729350). K.E.K. was supported by a grant from National Science Foundation and the Hungarian Scientific Research Fund, OTKA NK-68578. The opinions expressed are those of the authors and not necessarily those of NIDA. Authors are thankful to Ms. Margie Colie for her assistance with the manuscript.

PY - 2008/8

Y1 - 2008/8

N2 - Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and μ opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

AB - Prolonged opioid exposure increases the expression of cholecystokinin (CCK) and its receptors in the central nervous system (CNS), where CCK may attenuate the antinociceptive effects of opioids. The complex interactions between opioid and CCK may play a role in the development of opioid tolerance. We designed and synthesized cyclic disulfide peptides and determined their agonist properties at opioid receptors and antagonist properties at CCK receptors. Compound 1 (Tyr-c[d-Cys-Gly-Trp-Cys]-Asp-Phe-NH2) showed potent binding and agonist activities at δ and μ opioid receptors but weak binding to CCK receptors. The NMR structure of the lead compound displayed similar conformational features of opioid and CCK ligands.

KW - Bifunctional peptides

KW - G-Protein coupled receptors

KW - Multivalent ligands

KW - NMR conformation

KW - Overlapping pharmacophores

KW - Pain

KW - Tolerance

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JO - Peptides

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ER -

Structure-activity relationships of bifunctional cyclic disulfide peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors

Abstract

Keywords

ASJC Scopus subject areas

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