Agonist effects of zinterol at the mouse and human β3-adrenoceptor
| Autor: | Ekaterina Chernogubova, Roger J. Summers, Dana S. Hutchinson, Tore Bengtsson, Masaaki Sato |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Agonist
medicine.medical_specialty Adrenergic receptor medicine.drug_class Glucose uptake Adrenergic beta-3 Receptor Agonists CHO Cells Biology Mice chemistry.chemical_compound Cricetulus Adipose Tissue Brown Cricetinae Internal medicine Adipocytes Cyclic AMP medicine Animals Humans Albuterol Cloning Molecular Zinterol Receptor Beta (finance) Mice Knockout Pharmacology Chinese hamster ovary cell Isoproterenol General Medicine Adrenergic beta-Agonists Glucose Endocrinology chemistry Ethanolamines Receptors Adrenergic beta-3 Extracellular Space |
| Zdroj: | Naunyn-Schmiedeberg's Archives of Pharmacology. 373:158-168 |
| ISSN: | 1432-1912 0028-1298 |
| Popis: | The present study investigates the action of zinterol at beta(3)-adrenoceptors. We used mouse primary brown adipocytes and Chinese hamster ovary (CHO-K1) cells expressing the mouse or human beta(3)-adrenoceptor. Zinterol was a full agonist at increasing cyclic AMP levels in primary brown adipocytes (which express beta(1)- and beta(3)-adrenoceptors but not beta(2)-adrenoceptors), and this effect was almost totally abolished in adipocytes derived from beta(3)-adrenoceptor knock-out (KO) mice. Zinterol was also a full agonist at increasing another biological end-point, glucose uptake in brown adipocytes. This effect was reduced in adipocytes derived from beta(3)-adrenoceptor KO mice, with the remaining response sensitive to beta(1)-adrenoceptor antagonism. To determine whether the effect of zinterol on beta(3)-adrenoceptors in primary brown adipocytes can be replicated in a recombinant system, we used CHO-K1 cells expressing the mouse or human beta(3)-adrenoceptor. Zinterol was a full agonist at mouse and human receptors with respect to increasing cyclic AMP levels, with pEC(50) values similar to that of the selective beta(3)-adrenoceptor agonist (R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate (CL316243) at the mouse receptor. At the human receptor, zinterol was more potent at increasing cyclic AMP levels than CL316243. In cytosensor microphysiometer studies, zinterol was a full agonist for increases in extracellular acidification rates at the mouse and human beta(3)-adrenoceptor. Therefore, we have shown that zinterol is a potent, high-efficacy beta(3)-adrenoceptor agonist at the endogenous mouse beta(3)-adrenoceptor in primary brown adipocytes and at the cloned mouse and human beta(3)-adrenoceptor expressed in CHO-K1 cells. Zinterol is therefore one of few beta-adrenoceptor agonists with high potency and efficacy at the human beta(3)-adrenoceptor. |
| Databáze: | OpenAIRE |
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