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Agonist effects of zinterol at the mouse and human β3-adrenoceptor

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Abstract

The present study investigates the action of zinterol at β3-adrenoceptors. We used mouse primary brown adipocytes and Chinese hamster ovary (CHO-K1) cells expressing the mouse or human β3-adrenoceptor. Zinterol was a full agonist at increasing cyclic AMP levels in primary brown adipocytes (which express β1- and β3-adrenoceptors but not β2-adrenoceptors), and this effect was almost totally abolished in adipocytes derived from β3-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 β3-adrenoceptor KO mice, with the remaining response sensitive to β1-adrenoceptor antagonism. To determine whether the effect of zinterol on β3-adrenoceptors in primary brown adipocytes can be replicated in a recombinant system, we used CHO-K1 cells expressing the mouse or human β3-adrenoceptor. Zinterol was a full agonist at mouse and human receptors with respect to increasing cyclic AMP levels, with pEC50 values similar to that of the selective β3-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 β3-adrenoceptor. Therefore, we have shown that zinterol is a potent, high-efficacy β3-adrenoceptor agonist at the endogenous mouse β3-adrenoceptor in primary brown adipocytes and at the cloned mouse and human β3-adrenoceptor expressed in CHO-K1 cells. Zinterol is therefore one of few β-adrenoceptor agonists with high potency and efficacy at the human β3-adrenoceptor.

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Abbreviations

CHO-K1:

Chinese hamster ovary

CGP12177A:

(+)-4-(3-t-butylamino-2-hydroxy-propoxy)benzimidazol-2-one

CL316243:

(R, R)-5-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]-amino]-propyl]1,3-benzodioxole-2,2-dicarboxylate

ECAR:

extracellular acidification rate

ICI89406:

N-[2-[3-(2-Cyanophenoxy)-2-hydroxypropylamino]ethyl-N´-phenylurea

KO:

knock-out

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Acknowledgements

We thank Martina Helin, Tina Wallin and Maria Uustalu for technical assistance. This study was supported by the Swedish Natural Science Research Council, the Tore Nilsons Stiftelse for Medicinsk Forskening, the Jeanssonska funds and National Health and Medical Research Council of Australia Project Grant 236884. Prof Roger Summers was the 2003 Tage Erlander Gästprofessor of the Swedish Natural Science Research Council and Dr Dana S Hutchinson is a CJ Martin Fellow of the National Health and Medical Research Council of Australia.

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  1. Ekaterina Chernogubova

    Present address: Gustaf V:s Forskningsinstitut, Karolinska Universitetssjukhuset, Solna M1, 17176, Stockholm, Sweden

Authors and Affiliations

  1. Department of Physiology, The Wenner-Gren Institute, Arrhenius Laboratory F3, Stockholm University, 10691, Stockholm, Sweden

    Dana S. Hutchinson, Ekaterina Chernogubova & Tore Bengtsson

  2. Department of Pharmacology, Monash University, PO Box 13E, Victoria, 3800, Australia

    Dana S. Hutchinson, Masaaki Sato & Roger J. Summers

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  1. Dana S. Hutchinson
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Correspondence to Tore Bengtsson.

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Hutchinson, D.S., Chernogubova, E., Sato, M. et al. Agonist effects of zinterol at the mouse and human β3-adrenoceptor. Naunyn Schmied Arch Pharmacol 373, 158–168 (2006). https://doi.org/10.1007/s00210-006-0056-3

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