Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain

Sara M. Hall, Lindsay LeBaron, Cyf Ramos-Colon, Chaoling Qu, Jennifer Yanhua Xie, Frank Porreca, Josephine Lai, Yeon Sun Lee, Victor J Hruby

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Dynorphin A (Dyn A) is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors with a preference for the kappa receptor but also neuroexcitatory effects, which cause hyperalgesia. We have shown that the neuroexcitatory effects are mediated through bradykinin (BK) receptors and that intrathecal (i.th.) administration of our lead ligand 1, [des-Arg7]-Dyn A-(4-11), which shows good binding affinity (IC50 = 150 nM) at the BK receptors, blocks Dyn A-induced hyperalgesia in naïve animals and reverses thermal and tactile hypersensitivities in a dose-dependent manner in nerve-injured animals. However, 1 has a serious drawback as a potential drug candidate for the treatment of neuropathic pain because of its susceptibility to enzymatic degradation. In an effort to increase its stability, we modified ligand 1 using non-natural amino acids and found that analogues substituted at or near the N-terminus with a d-isomer retain binding at the receptor and provide a large increase in stability. In particular when Leu5 was modified, with either the d-isomer or N-methylation, there was a large increase in stability (t1/2 = 0.7-160 h in rat plasma) observed. From these studies, we have developed a very stable Dyn A analogue 16, [d-Leu5,des-Arg7]-Dyn A-(4-11), that binds to BK receptors (IC50 = 130 nM) in the same range as ligand 1 and shows good antihyperalgesic effects in both naïve rats and L5/L6 spinal nerve ligation rats.

Original languageEnglish (US)
Pages (from-to)1746-1752
Number of pages7
JournalACS Chemical Neuroscience
Volume7
Issue number12
DOIs
StatePublished - Dec 21 2016

Fingerprint

Bradykinin Receptors
Dynorphins
Neuralgia
Ligands
Rats
Hyperalgesia
Isomers
Inhibitory Concentration 50
Animals
Therapeutics
Spinal Nerves
kappa Opioid Receptor
Methylation
Touch
Opioid Receptors
Ligation
Hypersensitivity
Hot Temperature
Plasmas
Amino Acids

Keywords

  • Antihyperalgesic effect
  • Bradykinin receptors
  • Neuropathic pain
  • Non-opioid dynorphin A
  • Peptide stability
  • Structure-activity relationship

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain. / Hall, Sara M.; LeBaron, Lindsay; Ramos-Colon, Cyf; Qu, Chaoling; Xie, Jennifer Yanhua; Porreca, Frank; Lai, Josephine; Lee, Yeon Sun; Hruby, Victor J.

In: ACS Chemical Neuroscience, Vol. 7, No. 12, 21.12.2016, p. 1746-1752.

Research output: Contribution to journalArticle

Hall, Sara M. ; LeBaron, Lindsay ; Ramos-Colon, Cyf ; Qu, Chaoling ; Xie, Jennifer Yanhua ; Porreca, Frank ; Lai, Josephine ; Lee, Yeon Sun ; Hruby, Victor J. / Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain. In: ACS Chemical Neuroscience. 2016 ; Vol. 7, No. 12. pp. 1746-1752.
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abstract = "Dynorphin A (Dyn A) is a unique endogenous ligand that possesses well-known neuroinhibitory effects via opioid receptors with a preference for the kappa receptor but also neuroexcitatory effects, which cause hyperalgesia. We have shown that the neuroexcitatory effects are mediated through bradykinin (BK) receptors and that intrathecal (i.th.) administration of our lead ligand 1, [des-Arg7]-Dyn A-(4-11), which shows good binding affinity (IC50 = 150 nM) at the BK receptors, blocks Dyn A-induced hyperalgesia in na{\"i}ve animals and reverses thermal and tactile hypersensitivities in a dose-dependent manner in nerve-injured animals. However, 1 has a serious drawback as a potential drug candidate for the treatment of neuropathic pain because of its susceptibility to enzymatic degradation. In an effort to increase its stability, we modified ligand 1 using non-natural amino acids and found that analogues substituted at or near the N-terminus with a d-isomer retain binding at the receptor and provide a large increase in stability. In particular when Leu5 was modified, with either the d-isomer or N-methylation, there was a large increase in stability (t1/2 = 0.7-160 h in rat plasma) observed. From these studies, we have developed a very stable Dyn A analogue 16, [d-Leu5,des-Arg7]-Dyn A-(4-11), that binds to BK receptors (IC50 = 130 nM) in the same range as ligand 1 and shows good antihyperalgesic effects in both na{\"i}ve rats and L5/L6 spinal nerve ligation rats.",
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AU - Qu, Chaoling

AU - Xie, Jennifer Yanhua

AU - Porreca, Frank

AU - Lai, Josephine

AU - Lee, Yeon Sun

AU - Hruby, Victor J

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