Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors

Yeon Sun Lee; Robert Kupp; Michael V. Remesic; Cyf Ramos-Colon; Sara M Hall; Christopher Chan; David Rankin; Josephine Lai; Frank Porreca; Victor J Hruby

doi:10.1111/cbdd.12789

Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors

Yeon Sun Lee, Robert Kupp, Michael V. Remesic, Cyf Ramos-Colon, Sara M Hall, Christopher Chan, David Rankin, Josephine Lai, Frank Porreca, Victor J Hruby

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

2 Scopus citations

Abstract

As a unique endogenous opioid ligand, dynorphin A shows paradoxical neuroexcitatory effects at bradykinin receptors, and the effects are known to be amplified by the upregulation of dynorphin A under chronic pain and inflammatory conditions. In our earlier structure–activity relationship studies, the amphipathic dynorphin A fragment, [Des-Arg⁷]-Dyn A-(4–11), was identified as a pharmacophore for the bradykinin receptors along with key structural features. Here, further modifications of the pharmacophore showed that the position of a Pro residue is also an important feature because of its role in making (or disrupting) a β-turn or 3₁₀ helix structure which is crucial for receptor recognition.

Original language	English (US)
Pages (from-to)	615-619
Number of pages	5
Journal	Chemical Biology and Drug Design
DOIs	https://doi.org/10.1111/cbdd.12789
State	Published - Oct 1 2016

Keywords

amphipathicity
bradykinin receptors
chronic pain
non-opioid dynorphin A
proline
structure–activity relationship

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Organic Chemistry

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10.1111/cbdd.12789

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title = "Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors",

abstract = "As a unique endogenous opioid ligand, dynorphin A shows paradoxical neuroexcitatory effects at bradykinin receptors, and the effects are known to be amplified by the upregulation of dynorphin A under chronic pain and inflammatory conditions. In our earlier structure–activity relationship studies, the amphipathic dynorphin A fragment, [Des-Arg7]-Dyn A-(4–11), was identified as a pharmacophore for the bradykinin receptors along with key structural features. Here, further modifications of the pharmacophore showed that the position of a Pro residue is also an important feature because of its role in making (or disrupting) a β-turn or 310 helix structure which is crucial for receptor recognition.",

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doi = "10.1111/cbdd.12789",

language = "English (US)",

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AU - Lee, Yeon Sun

AU - Kupp, Robert

AU - Remesic, Michael V.

AU - Ramos-Colon, Cyf

AU - Hall, Sara M

AU - Chan, Christopher

AU - Rankin, David

AU - Lai, Josephine

AU - Porreca, Frank

AU - Hruby, Victor J

PY - 2016/10/1

Y1 - 2016/10/1

N2 - As a unique endogenous opioid ligand, dynorphin A shows paradoxical neuroexcitatory effects at bradykinin receptors, and the effects are known to be amplified by the upregulation of dynorphin A under chronic pain and inflammatory conditions. In our earlier structure–activity relationship studies, the amphipathic dynorphin A fragment, [Des-Arg7]-Dyn A-(4–11), was identified as a pharmacophore for the bradykinin receptors along with key structural features. Here, further modifications of the pharmacophore showed that the position of a Pro residue is also an important feature because of its role in making (or disrupting) a β-turn or 310 helix structure which is crucial for receptor recognition.

AB - As a unique endogenous opioid ligand, dynorphin A shows paradoxical neuroexcitatory effects at bradykinin receptors, and the effects are known to be amplified by the upregulation of dynorphin A under chronic pain and inflammatory conditions. In our earlier structure–activity relationship studies, the amphipathic dynorphin A fragment, [Des-Arg7]-Dyn A-(4–11), was identified as a pharmacophore for the bradykinin receptors along with key structural features. Here, further modifications of the pharmacophore showed that the position of a Pro residue is also an important feature because of its role in making (or disrupting) a β-turn or 310 helix structure which is crucial for receptor recognition.

KW - amphipathicity

KW - bradykinin receptors

KW - chronic pain

KW - non-opioid dynorphin A

KW - proline

KW - structure–activity relationship

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JO - Chemical Biology and Drug Design

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Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors

Abstract

Keywords

ASJC Scopus subject areas

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