FUNCTIONAL-STUDIES OF THE FIRST SELECTIVE BETA(3)-ADRENERGIC RECEPTORANTAGONIST SR 59230A IN RAT BROWN ADIPOCYTES

The SS-enantiomer 2,3,4-tetrahydronaphth-1-ylaminol]-(2S)-2-propanol o xalate (SR 59230A) is proposed to be the first beta(3)-adrenergic rece ptor antagonist. The present work shows that SR 59230A, unlike its ina ctive RR-enantiomer (SR 59483), antagonized a typical beta(3)-adrenerg ic response in vitro, i.e., SR 58611A, the yl]amino]-5,6,7,8-tetrahydr onaphth-2-yl]oxyacetate hydrochloride- or 3-t-butylamino-2-hydroxyprop oxy)benzimidazol-2-one (CGP 12177)-stimulated synthesis of cAMP in rat brown adipose tissue membranes, with pK(B) values of 8.87 +/- 0.12 an d 8.20 +/- 0.15. In addition, SR 59230A had no antagonistic effect on forskolin-induced cAMP accumulation in rat interscapular brown adipose tissue. SR 59230A, in contrast to the selective beta(1)- and beta(2)- adrenoceptor antagonists -methyl-4-trifluoromethyl-2-imidazolyl)-pheno xy]-2 propanol and -4-yloxy)-3-isopropylaminobutan-2-ol-hydrochloride did not counteract the cAMP production induced by (-)-isoprenaline or norepinephrine (NE) in rat brain areas rich in beta(1)- or beta(2)-adr enoceptors, such as frontal cortex and cerebellum. Moreover, in prolif erating brown fat cells, in which the beta(1)-adrenoceptor is the only beta-adrenergic subtype coupled to cAMP production, SR 59230A did not modify the production of cAMP induced by NE, whereas CGP 12177 did. I n confluent brown fat cells, in which the beta(3)-adrenoceptor is the functional beta-adrenergic subtype coupled to adenylyl cyclase, SR 592 30A antagonized the NE-induced cAMP accumulation and glycerol release without affecting their basal values, whereas CGP 12177, which per se stimulated cAMP accumulation and glycerol release, did not change the NE-induced increase of either parameter. Finally, SR 59230A concentrat ion-dependently counteracted the NE-stimulated synthesis of uncoupling protein gene in confluent brown fat cells, which is considered mainly a result of selective stimulation of beta(3)-adrenoceptors. These res ults provide evidence that the new selective beta(3)-adrenoceptor anta gonist can contribute considerably to functional characterization of t he beta(3)-adrenoceptors.