Anti-obesity and anti-diabetic activities of a new beta(3) adrenergic receptor agonist, (S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxpropyl)]amino]ethyl]-1-propenyl]phenoxy] acetic acid ethanedioic acid (SWR-0342SA), in KK-A(y) mice

We investigated the beta-adrenergic receptor (AR) agonistic activities in r ats and humans, and the anti-obesity and anti-diabetic activities in KK-A(y ) mice, of a new beta(3)-AR agonist, SWR-0342SA ((S)-(Z)-[4-[[1-[2-[(2-hydr oxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl]phenoxy] acetic acid ethanedio ic acid). With regards to its PAR agonistic activity in rats, SWR-0342SA st imulated the atrial beating rate (beta(1)-AR activity) and white adipocyte lipolysis (beta(3)-AR activity), but did not induce uterine muscle relaxati on (beta(2)-AR activity). The beta(3)-AR agonistic activity of SWR-0342SA w as about 20 times stronger than its beta(1)-AR agonistic activity. Similarl y, SWR-0342SA enhanced the accumulation of cAMP in Chinese hamster ovary (C HO) cells expressing human beta(1)- and beta(3)-ARs, while having no effect in CHO cells expressing beta(2)-ARs. Adenylyl cyclase stimulation by SWR-0 342SA in CHO cells expressing beta(3)-ARs was about 35 times higher than th at in CHO cells expressing beta(1)-ARs. With regards to anti-obesity and an ti-diabetic activities, SWR-0342SA had no effect on body weight or food int ake, but slightly decreased the fat pads weight in KK-A(y) mice, an animal model of obesity and non-insulin-dependent diabetes mellitus (NIDDM). On th e other hand, SWR-0342SA significantly decreased both blood glucose (to abo ut 46% of control) and serum insulin levels (to about 40% of control) in KK -A(y) mice. These results indicated that SWR-0342SA is a selective beta(3)-AR agonist, and possesses potent anti-diabetic activity, and that the anti-obesity acti vity is inferior to the anti-diabetic activity.