Cyclic non-opioid dynorphin A analogues for the bradykinin receptors. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Lee, Yeon Sun; Remesic, Michael; Ramos-Colon, Cyf; Hall, Sara M.; Kuzmin, Alexander; Rankin, David; Porreca, Frank; Lai, Josephine; Hruby, Victor J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 22(2016)
• Page Start: 5513
• Page End: 5516
• Publication Date: 2016-11-15
• Subjects: BBB blood brain barrier -- BK bradykinin -- Boc t-butyloxycarbonyl -- BR bradykinin receptor -- CNS central nervous system -- DALKD [des-Arg10, Leu9]-kallidin -- DIPEA diisopropylethylamine -- DMF N, N-dimethylformamide -- Dyn A dynorphin A -- Fmoc fluorenylmethyloxycarbonyl -- HBTU 2-(1H-benzotriazole-1-yl)-1, 1, 3, 3-tetramethylaminium hexafluorophosphate -- HOBt N-hydroxybenzotriazole -- i.pl. intraplantar -- MS mass spectroscopy -- Pbf 2, 2, 4, 6, 7-pentamethyldihydrobenzofuran-5-sulfonyl -- RP-HPLC reversed-phase high performance liquid chromatography -- SNL spinal nerve ligation -- SPPS solid phase peptide synthesis -- Pip 2-phenylisopropyl -- TFA trifluoroacetic acid -- TIS triisopropylsilane -- WDR wide dynamic range; Cyclic ligands -- Non-opioid dynorphin A -- Amphipathicity -- Bradykinin receptors -- Structure–activity relationship -- Metabolic stability; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.10.010
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure–activity relationships study on Dyn A identified lead ligands1 and4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma ( t 1/2 <1 h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand4 afforded a cyclic Dyn A analogue5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability ( t 1/2 >5 h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.