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Pharmacological Effects of KR60886, A New β3 Adrenoceptor Agonist  

Lee, Sang-Suk (Korea Research Institute of Chemical Technology Medicinal Science Division)
Yang, Sung-Don (Korea Research Institute of Chemical Technology Medicinal Science Division)
Ha, Jae-Du (Korea Research Institute of Chemical Technology Medicinal Science Division)
Choi, Joong-Kwon (Korea Research Institute of Chemical Technology Medicinal Science Division)
Cheon, Hyae-Gyeong (Korea Research Institute of Chemical Technology Medicinal Science Division)
Publication Information
Biomolecules & Therapeutics / v.12, no.4, 2004 , pp. 215-220 More about this Journal
Abstract
In an attempt to develop new anti-diabetic agents, a series of aryloxypropanolamine derivatives was synthesized to serve as ${\beta}_3$ adrenoceptor agonists. Among these derivatives, 1-{1-methyl-3-[4-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)phenyl]propylamino}-3-phenoxy-2-propanol (KR60886) possessed a high affinity for the ${\beta}_3$ adrenoceptor (Ki = 28 nM) and moderate affinities for ${\beta}_1$ and ${\beta}_2$ adrenoceptors (Ki = 95 nM and 100 nM, respectively). In addition, KR60886 stimulated cAMP production with an EC$_{50}$ of 0.4 ${\mu}M$, confirming its agonistic activity for the ${\beta}_3$ adrenoceptor. In vivo activities of KR60886 were examined by using a fat-fed/streptozotocin (STZ)-treated rat model and the ob/ob mouse model. Oral administration of KR60886 (10 mg/kg) for 3 days (b.i.d.) to fat-fed/STZ-treated rats significantly lowered plasma glucose levels and reduced plasma free fatty acid concentrations. Similarly, KR60886 treatment (10 mg/kg/day for 7 d) resulted in a reduction of plasma glucose concentrations in ob/ob mice. The present study suggests that KR60886 is a potent ${\beta}_3$ receptor agonist with in vivo anti-diabetic properties.
Keywords
null; selectivity; anti-diabetic activity; ob/ob mouse; fat-fed/STZ-treated rat;
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1 Arch, J. R. S., Ainsworth, A. T., Cawthome, M. A., Piercy, V., Sennitt, M.V., Thody, V.E., Wilson, C., Wilson, S. (1984). Atypical $\beta$-adrenoceptor on brown adipocytes as target for antiobesity drugs. Nature 309, 163-165   DOI   ScienceOn
2 Arch, J.R.S., Kaumann, A.J. (1993). $\beta$$_3$ and atypical $\beta$-adrenoceptors. Med. Res. Rev. 13,663-729   DOI   ScienceOn
3 Emorine, L. J., Marullo, S., Briend-Sutren, M.-M., Patey, G., Tate, K., Delavier-Klutchko, C., Strosberg, A. D. (1989). Molecular characterization of the human $\beta$$_3$ adrenergic receptor. Science 245, 1118-1121   DOI
4 Esbenshade, T.A., Theroux, T.L., Granneman, J.G., Minneman, K.P. (1992). Coexisting beta 1 and atypical beta adrenergic receptors cause reductant increases in cyclic AMP in human neuroblastoma cells. Mol. Pharmacol. 42,753-759
5 Guan, X.M., Amend, A., Strader, C.D. (1995). Determination of structural domains for G protein coupling and ligand binding in $\beta$$_3$ adrenergic receptor. Mol. Pharmacol. 48, 492-498
6 Himms-Hagen, J., Danforth, E. Jr. (1996). The potential role of $\beta$$_3$ adrenoceptor agonists in the treatment of obesity and diabetes. Curr. Opin. Endoerin. Diabetes 3, 59-65   DOI
7 Lowell, B. B., Flier, J. S. (1997). Brown adipose tissue, $\beta$$_3$ adrenergic receptors and obesity. Annu. Rev. Med. 43, 307-316
8 Curran, P., Fishman, P.H. (1996). Endogeneous beta 3 but not beta-I adrenergic receptors are resistant to agonist-mediated regulation in human SK-N-MC neurotumor cells. Cell signal 8, 355-364   DOI   ScienceOn
9 Blin, N., Nahmias, C., Drumare, M.P., Strosberg, A.D. (1994). Mediation of most atypical effects by species homologues of the $\beta_{3}$-adrenoceptor. Br. J. Pharmacol. 112, 911-919   DOI   ScienceOn
10 Bloom, J.D., Claus, T.H. (1994). CL316,243. Drugs of Future 19, 23-26   DOI
11 Emorine, L., Blin, N., Strosberg, A.D. (1994). The human $\beta$$_3$ adrenoceptor: the search for a physiological function. TiPS 15 3-7
12 Weber, A.E. (1998). $\beta$$_3$ adrenergic receptor agonists for the treatment of obesity. Ann. Rep. Med. Chem. 33, 193-202   DOI
13 Reed, M.J., Meszaros, K, Entes, L.J., Claypool, M.D., Pinkett, J.G., Gadbois, T.M., Reaven, G.M. (2000). A new rat model of type 2 diabetes: the fat-fed, streptozotocin-treated rat. Metabolism 49, 1390-1394   DOI   ScienceOn
14 Rosenbaum, M., Malbon, C.C., Hirsch, J., Leibel, R.L. (1993). Lack of $\beta$$_3$ adrenergic effect on lipolysis in human subcutaneous adipose tissue. J. Clin. Endocrinol. Metab. 77, 352-355   DOI   ScienceOn
15 Strosberg, AD. (1997). Structure and function of the $\beta$$_3$ adrenergic receptor. Annu. Rev. Pharmacol. Toxicol. 37, 421-450   DOI   ScienceOn
16 Weyer, C., Gautier, J.F., Danforth, E. (1999). Development of beta3-adrenoceptor agonists for the treatment of obesity and diabetes-An update. Diabetes Metab. 25, 11-21
17 Ok, H.O., Reigle, L.B., Candelore, M.R., Cascieri, M.A., Colwell, L.F., Deng, L., Feeney, W.P., Forrest, M.J., Hom, G.J., MacIntyre, D.E., Strader, C.D., Tota, L., Wang, P., Wyvratt, M.J., Fisher, M.H., Weber, A.E. (2000). Substituted oxazole benzenesulfonamides as potent human $\beta$$_3$ adrenergic receptor agonists. Bioorg. Med. Chem. Lett. 10, 1531-1534   DOI   ScienceOn
18 Mathvink, R.J., Tolman, J.S., Chitty, D., Candelore, M.R., Cascieri, M.A., Colwell, L.F., Deng, L., Feeney, W.P., Forrest, M.J., Hom, G.J., MacIntyre, D.E., Miller, R.R., Steams, R.A., Tom, L., Wyvratt, M.J., Fisher, M.H., Weber, A.E. (2000). Discovery of a potent, orally bioavailable $\beta$$_3$ adrenoceptor agonist, (R)-N-[4-[2-[[2hydroxy-2-(3-pyridinyl-ethyl)arninoethyl]amino]ethyl]phenyl]-4-[4-[4-(trifluoromethyI)phenyI]thiazol-2-yl]benzenesulfonamide. J. Med. Chern. 43, 3832-3836   DOI   ScienceOn