Identification of the hypertension drug niflumic acid as a glycine receptor inhibitor
| Autor: | Hiromi Hirata, Ayato Sato, Motonari Uesugi, Daishi Ito, Yoshinori Kawazoe |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Embryo Nonmammalian Nifedipine Phenotypic screening Vasodilator Agents Glycine lcsh:Medicine Convulsants Pharmacology Neurotransmission Synaptic Transmission Article Membrane Potentials Xenopus laevis 03 medical and health sciences chemistry.chemical_compound Receptors Glycine 0302 clinical medicine Postsynaptic potential Developmental biology medicine Animals Picrotoxin lcsh:Science Glycine receptor Zebrafish Multidisciplinary Drug discovery Calcium channel Anti-Inflammatory Agents Non-Steroidal Niflumic acid lcsh:R Niflumic Acid Strychnine 030104 developmental biology Drug screening chemistry Embryogenesis Oocytes Female lcsh:Q 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-8 (2020) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-70983-2 |
| Popis: | Glycine is one of the major neurotransmitters in the brainstem and the spinal cord. Glycine binds to and activates glycine receptors (GlyRs), increasing Cl− conductance at postsynaptic sites. This glycinergic synaptic transmission contributes to the generation of respiratory rhythm and motor patterns. Strychnine inhibits GlyR by binding to glycine-binding site, while picrotoxin blocks GlyR by binding to the channel pore. We have previously reported that bath application of strychnine to zebrafish embryos causes bilateral muscle contractions in response to tactile stimulation. To explore the drug-mediated inhibition of GlyRs, we screened a chemical library of ~ 1,000 approved drugs and pharmacologically active molecules by observing touch-evoked response of zebrafish embryos in the presence of drugs. We found that exposure of zebrafish embryos to nifedipine (an inhibitor of voltage-gated calcium channel) or niflumic acid (an inhibitor of cyclooxygenase 2) caused bilateral muscle contractions just like strychnine-treated embryos showed. We then assayed strychnine, picrotoxin, nifedipine, and niflumic acid for concentration-dependent inhibition of glycine-mediated currents of GlyRs in oocytes and calculated IC50s. The results indicate that all of them concentration-dependently inhibit GlyR in the order of strychnine > picrotoxin > nifedipine > niflumic acid. |
| Databáze: | OpenAIRE |
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