Cyclic non-opioid dynorphin A analogues for the bradykinin receptors
| Autor: | Frank Porreca, David Rankin, Alexander Kuzmin, Josephine Lai, Michael Remesic, Victor J. Hruby, Sara M. Hall, Cyf Ramos-Colon, Yeon Sun Lee |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry Pharmaceutical Science Bradykinin Inflammation Pharmacology Ligands Dynorphins Biochemistry Article Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Drug Discovery medicine Animals Amino Acid Sequence Receptor Molecular Biology Bradykinin Receptor Antagonists Endogenous opioid Receptors Bradykinin Organic Chemistry Dynorphin A Analgesics Non-Narcotic Nerve injury Rats 030104 developmental biology chemistry Opioid Cyclization Hyperalgesia Molecular Medicine medicine.symptom 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 26:5513-5516 |
| ISSN: | 0960-894X |
| Popis: | 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 < 1 h) 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 > 5 h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development. |
| Databáze: | OpenAIRE |
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