Arizona Health Sciences

Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord.

TitleDiscovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord.
Publication TypeJournal Article
Year of Publication2014
AuthorsLee YSun, Muthu D, Hall SM, Ramos-Colon C, Rankin D, Hu J, Sandweiss AJ, De Felice M, Xie JYanhua, Vanderah TW, Porreca F, Lai J, Hruby VJ
JournalJ Am Chem Soc
Volume136
Issue18
Pagination6608-16
Date Published2014 May 7
ISSN1520-5126
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.

DOI10.1021/ja501677q
Alternate JournalJ. Am. Chem. Soc.
PubMed ID24742335
PubMed Central IDPMC4021566
Grant ListHHSN-271-2008-025C / / PHS HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
P01DA006284 / DA / NIDA NIH HHS / United States
R01 DA011823 / DA / NIDA NIH HHS / United States
R01 DA012656 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Victor Hruby, Ph.D.
Josephine Lai , Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD
Yanhua Xie, Ph.D.