Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the Î° Opioid Receptor

Cyf N. Ramos-Colon; Yeon Sun Lee; Michael Remesic; Sara M. Hall; Justin Lavigne; Peg Davis; Alexander J. Sandweiss; Mary I. McIntosh; Jessica Hanson; Tally M. Largent-Milnes; Todd W. Vanderah; John Streicher; Frank Porreca; Victor J. Hruby

doi:10.1021/acs.jmedchem.6b01411

Structure-Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the Î° Opioid Receptor

Cyf N. Ramos-Colon, Yeon Sun Lee, Michael Remesic, Sara M. Hall, Justin Lavigne, Peg Davis, Alexander J. Sandweiss, Mary I. McIntosh, Jessica Hanson, Tally M. Largent-Milnes, Todd W. Vanderah, John Streicher, Frank Porreca, Victor J. Hruby

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

5 Scopus citations

Abstract

Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the Î° opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg⁷ residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg⁷]Dyn A analogues found that Arg⁷ is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg⁷]Dyn A(1-9)-NH₂ is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.

Original language	English (US)
Pages (from-to)	10291-10298
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	59
Issue number	22
DOIs	https://doi.org/10.1021/acs.jmedchem.6b01411
State	Published - Nov 23 2016

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Ramos-Colon, C. N., Lee, Y. S., Remesic, M., Hall, S. M., Lavigne, J., Davis, P., Sandweiss, A. J., McIntosh, M. I., Hanson, J., Largent-Milnes, T. M., Vanderah, T. W., Streicher, J., Porreca, F., & Hruby, V. J. (2016). Structure-Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the Î° Opioid Receptor. Journal of Medicinal Chemistry, 59(22), 10291-10298. https://doi.org/10.1021/acs.jmedchem.6b01411

Structure-Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the Î° Opioid Receptor. / Ramos-Colon, Cyf N.; Lee, Yeon Sun; Remesic, Michael; Hall, Sara M.; Lavigne, Justin; Davis, Peg; Sandweiss, Alexander J.; McIntosh, Mary I.; Hanson, Jessica; Largent-Milnes, Tally M.; Vanderah, Todd W.; Streicher, John; Porreca, Frank ; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 59, No. 22, 23.11.2016, p. 10291-10298.

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

Ramos-Colon, CN, Lee, YS, Remesic, M, Hall, SM, Lavigne, J, Davis, P, Sandweiss, AJ, McIntosh, MI, Hanson, J, Largent-Milnes, TM, Vanderah, TW, Streicher, J, Porreca, F & Hruby, VJ 2016, 'Structure-Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the Î° Opioid Receptor', Journal of Medicinal Chemistry, vol. 59, no. 22, pp. 10291-10298. https://doi.org/10.1021/acs.jmedchem.6b01411

Ramos-Colon, Cyf N. ; Lee, Yeon Sun ; Remesic, Michael ; Hall, Sara M. ; Lavigne, Justin ; Davis, Peg ; Sandweiss, Alexander J. ; McIntosh, Mary I. ; Hanson, Jessica ; Largent-Milnes, Tally M. ; Vanderah, Todd W. ; Streicher, John ; Porreca, Frank ; Hruby, Victor J. / Structure-Activity Relationships of [des-Arg⁷]Dynorphin A Analogues at the Î° Opioid Receptor. In: Journal of Medicinal Chemistry. 2016 ; Vol. 59, No. 22. pp. 10291-10298.

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title = "Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the {\^I}° Opioid Receptor",

abstract = "Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the {\^I}° opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.",

author = "Ramos-Colon, {Cyf N.} and Lee, {Yeon Sun} and Michael Remesic and Hall, {Sara M.} and Justin Lavigne and Peg Davis and Sandweiss, {Alexander J.} and McIntosh, {Mary I.} and Jessica Hanson and Largent-Milnes, {Tally M.} and Vanderah, {Todd W.} and John Streicher and Frank Porreca and Hruby, {Victor J.}",

note = "Funding Information: This work has been supported by U.S. Public Health Services, NIH, and NIDA (Grants RO1 DA 13449 and PO1 DA 006284).",

year = "2016",

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doi = "10.1021/acs.jmedchem.6b01411",

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T1 - Structure-Activity Relationships of [des-Arg7]Dynorphin A Analogues at the Î° Opioid Receptor

AU - Ramos-Colon, Cyf N.

AU - Lee, Yeon Sun

AU - Remesic, Michael

AU - Hall, Sara M.

AU - Lavigne, Justin

AU - Davis, Peg

AU - Sandweiss, Alexander J.

AU - McIntosh, Mary I.

AU - Hanson, Jessica

AU - Largent-Milnes, Tally M.

AU - Vanderah, Todd W.

AU - Streicher, John

AU - Porreca, Frank

AU - Hruby, Victor J.

N1 - Funding Information: This work has been supported by U.S. Public Health Services, NIH, and NIDA (Grants RO1 DA 13449 and PO1 DA 006284).

PY - 2016/11/23

Y1 - 2016/11/23

N2 - Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the Î° opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.

AB - Dynorphin A (Dyn A) is an endogenous ligand for the opioid receptors with preference for the Î° opioid receptor (KOR), and its structure-activity relationship (SAR) has been extensively studied at the KOR to develop selective potent agonists and antagonists. Numerous SAR studies have revealed that the Arg7 residue is essential for KOR activity. In contrast, our systematic SAR studies on [des-Arg7]Dyn A analogues found that Arg7 is not a key residue and even deletion of the residue does not affect biological activities at the KOR. In addition, it was also found that [des-Arg7]Dyn A(1-9)-NH2 is a minimum pharmacophore and its modification at the N-terminus leads to selective KOR antagonists. A lead ligand, 14, with high affinity and antagonist activity showed improved metabolic stability and could block antinociceptive effects of a KOR selective agonist, FE200665, in vivo, indicating high potential to treat KOR mediated disorders such as stress-induced relapse.

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