An innovative method for rapid characterisation of phospholipase C activity: SB242,084 competitively antagonises 5-HT 2C receptor-mediated [ 3 H]phosphatidylinositol depletion
| Autor: | Didier Cussac, Yann Quentric, Adrian Newman-Tancredi, Mark Millan |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Serotonin
Indoles medicine.drug_class Aminopyridines CHO Cells Biology Phosphatidylinositols chemistry.chemical_compound Cricetinae Receptor Serotonin 5-HT2C medicine Animals Humans Phosphatidylinositol Ergolines Inositol phosphate Receptor Mesulergine Pharmacology chemistry.chemical_classification Phospholipase C Antagonist General Medicine Receptor antagonist chemistry Biochemistry Competitive antagonist Receptors Serotonin Type C Phospholipases Serotonin Antagonists |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 361:221-223 |
| ISSN: | 1432-1912 0028-1298 |
| DOI: | 10.1007/s002109900178 |
| Popis: | 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-ylcarbamoyl] indoline (SB242,084) is a novel, selective 5-HT(2C) receptor antagonist, but its actions at these sites have been little characterised at the cellular level. We employed a rapid and innovative approach to investigate its functional activity at phospholipase C (PLC)-coupled human 5-HT(2C) receptors expressed in CHO cells. PLC activity was determined as a decrease in the [3H]phosphatidylinositol ([3H]PI) content of cell membranes. Serotonin (5-HT) stimulated [3H]PI depletion (pEC50=8.74), and SB242,084, like mesulergine, completely reversed this action of 5-HT (pK(B)=9.25 and 9.01, respectively). Further, in Schild analysis, SB242,084 behaved as a high affinity competitive antagonist, inducing a parallel, rightward displacement of the 5-HT stimulation isotherm without loss of maximum efficacy. The pA2 of 9.50 was similar to its binding affinity (pKi=9.38). SB242,084 also displayed antagonist properties when PLC activity was examined by conventional determination of [3H]inositol phosphate generation. Employing this parameter, the potency of SB242,084 (pK(B)=9.21) and that of mesulergine (pK(B)=9.06) closely resembled those determined by [3H]PI depletion. In conclusion, determination of [3H]PI depletion constitutes a useful and novel technique to characterise agonist and antagonist properties of ligands at PLC-coupled receptors. |
| Databáze: | OpenAIRE |
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