title: Discovery of amphipathic dynorphin A analogues to inhibit the neuroexcitatory effects of dynorphin A through bradykinin receptors in the spinal cord.
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.
authors.affiliation: Department of Chemistry and Biochemistry and ‡Department of Pharmacology, The University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Dhanasekaran
authors.initials: D
authors.lastname: Muthu
authors.forename: Sara M
authors.initials: SM
authors.lastname: Hall
authors.forename: Cyf
authors.initials: C
authors.lastname: Ramos-Colon
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.forename: Jackie
authors.initials: J
authors.lastname: Hu
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Sandweiss
authors.forename: Milena
authors.initials: M
authors.lastname: De Felice
authors.forename: Jennifer Yanhua
authors.initials: JY
authors.lastname: Xie
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000818:Animals; D004399:Dynorphins / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018002:Receptors, Bradykinin; D004399:Dynorphins
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