Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain
Autor: | Frank Porreca, Chaoling Qu, Lindsay LeBaron, Yeon Sun Lee, Cyf Ramos-Colon, Victor J. Hruby, Jennifer Y. Xie, Sara M. Hall, Josephine Lai |
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Rok vydání: | 2016 |
Předmět: |
Male
0301 basic medicine Physiology Cognitive Neuroscience Bradykinin Pharmacology Dynorphins Biochemistry κ-opioid receptor Article Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Stability Drug Discovery medicine Animals Humans Bradykinin receptor Receptor Receptors Bradykinin Brain Dynorphin A Cell Biology General Medicine Analgesics Non-Narcotic Ligand (biochemistry) Disease Models Animal 030104 developmental biology chemistry Opioid Hyperalgesia Neuralgia medicine.symptom 030217 neurology & neurosurgery Protein Binding medicine.drug |
Zdroj: | ACS Chemical Neuroscience. 7:1746-1752 |
ISSN: | 1948-7193 |
Popis: | 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. |
Databáze: | OpenAIRE |
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