Development of an N-acyl amino acid that selectively inhibits the glycine transporter 2 to produce analgesia in a rat model of chronic pain
| Autor: | Subhodeep Sarker, Tristan Rawling, Irina Vetter, Zachary J. Frangos, Arsalan Yousuf, MacDonald J. Christie, Renae M. Ryan, Susan Shimmon, Robert J. Vandenberg, Sarasa A. Mohammadi, Shannon N. Mostyn |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
medicine.medical_treatment
Medicinal & Biomolecular Chemistry Intraperitoneal injection Pharmacology Blood–brain barrier 01 natural sciences Article Rats Sprague-Dawley 03 medical and health sciences Glycine Plasma Membrane Transport Proteins Drug Discovery medicine Animals Humans Amino Acids 030304 developmental biology chemistry.chemical_classification 0303 health sciences Analgesics biology Chemistry Chronic pain Half-life medicine.disease 0104 chemical sciences Amino acid Rats 010404 medicinal & biomolecular chemistry Disease Models Animal medicine.anatomical_structure Blood-Brain Barrier Glycine transporter 2 Toxicity Microsome biology.protein Microsomes Liver Molecular Medicine Chronic Pain Half-Life |
| Popis: | © 2019 American Chemical Society. Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics, but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesizing lipid analogues with a range of amino acid head groups in both l- and d-configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl-d-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood-brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2). |
| Databáze: | OpenAIRE |
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