title: Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.
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 ligands 1 and 4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma (t1/2<1h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand 4 afforded a cyclic Dyn A analogue 5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability (t1/2>5h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA. Electronic address: yeon@email.arizona.edu.
authors.forename: Yeon Sun
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Remesic
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Cyf
authors.initials: C
authors.lastname: Ramos-Colon
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Hall
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kuzmin
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85719, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rankin
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85719, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ 85719, USA.
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D018712:Analgesics, Non-Narcotic / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D065168:Bradykinin Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D003500:Cyclization; D004399:Dynorphins / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D051381:Rats; D018002:Receptors, Bradykinin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D065168:Bradykinin Receptor Antagonists; D008024:Ligands; D018002:Receptors, Bradykinin; D004399:Dynorphins
keywords: Amphipathicity; Bradykinin receptors; Cyclic ligands; Metabolic stability; Non-opioid dynorphin A; Structure–activity relationship