ArticleJournal of the American Chemical Society2014
Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 29 citations in OpenAlex.
- The bradykinin system in stress and anxiety in humans and mice.Scientific reports · 2019Article
- Kininase 1 As a Preclinical Therapeutic Target for Kinin BFrontiers in pharmacology · 2017Article
- Discovery of Stable Non-opioid Dynorphin A Analogues Interacting at the Bradykinin Receptors for the Treatment of Neuropathic Pain.ACS chemical neuroscience · 2016Article
- Structure-Activity Relationships of [des-ArgJournal of medicinal chemistry · 2016Article
- Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.Bioorganic & medicinal chemistry letters · 2016Article
- Various modifications of the amphipathic dynorphin A pharmacophore for rat brain bradykinin receptors.Chemical biology & drug design · 2016Article
- The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective.Annual review of pharmacology and toxicology · 2016Review
- Dynorphin A analogs for the treatment of chronic neuropathic pain.Future medicinal chemistry · 2016Review
- Cyclic Opioid Peptides.Current medicinal chemistry · 2016Review
- Design, synthesis and biological evaluation of multifunctional ligands targeting opioid and bradykinin 2 receptors.Bioorganic & medicinal chemistry letters · 2015Article
- Modification of amphipathic non-opioid dynorphin A analogues for rat brain bradykinin receptors.Bioorganic & medicinal chemistry letters · 2015Article
- Structure-activity relationships of non-opioid [des-Arg(7)]-dynorphin A analogues for bradykinin receptors.Bioorganic & medicinal chemistry letters · 2014Article
- Narcotic bowel syndrome and opioid-induced constipation.Current gastroenterology reports · 2014Review
- Neuropathic plasticity in the opioid and non-opioid actions of dynorphin A fragments and their interactions with bradykinin B2 receptors on neuronal activity in the rat spinal cord.Neuropharmacology · 2014Article
- Effect of adenoviral delivery of prodynorphin gene on experimental inflammatory pain induced by formalin in rats.International journal of clinical and experimental medicine · 2014Article
- Blockade of non-opioid excitatory effects of spinal dynorphin A at bradykinin receptors.Receptors & clinical investigationArticle
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors. Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (KD), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure-activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A's biological activity, is not necessary, and that a type I β-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naïve rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.
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