ANTIDIABETIC AND ANTIOBESITY EFFECTS OF A HIGHLY SELECTIVE BETA(3)-ADRENOCEPTOR AGONIST (CL-316,243)

A third beta-adrenoceptor subtype has been cloned from the rat, mouse, and human genomes. The presence of these receptors primarily on adipo se tissue has raised the possibility that beta(3)-adrenoceptor selecti ve agonists may be useful antiobesity agents. CL 316,243 is a highly s elective beta(3)-agonist; it has a >30,000 to 1 beta(3)-to-beta(1)-adr enoceptor selectivity ratio and a 10,000 to 1 beta(3)-to-beta(2)-adren oceptor selectivity ratio in in vitro functional assays. In vivo, anim als were treated with CL 314,698, a diester prodrug of CL 316,243, whi ch is rapidly converted to CL 316,243. In obese (ob/ob) and diabetic ( db/db) mice, treatment with CL 314,698 reduced their hyperglycemia to the euglycemia of their lean littermates, and decreased plasma insulin levels. In obese mice, the compound also caused decreased weight gain despite increased food consumption, and the decreased weight was due to loss of fat while lean body mass was spared. CL 314,698 treatment a lso improved both glucose and insulin tolerance in obese mice, suggest ing that it decreased insulin resistance. CL 314,698 also prevented fu rther weight gain, without affecting food consumption, in rats previou sly made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while h aving no effect on plasma glucose, cholesterol, thyroxine, or T-3 leve ls or on skeletal muscle weight. Decreased weight gain without decreas ed food consumption suggested that CL 316,243 stimulated thermogenesis . Treatment of obese mice for 3 weeks with CL 316,243 increased thermo genesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 i s a potent, beta(3)-adrenoceptor selective agonist with thermogenic, a ntidiabetic, and antiobesity properties in several models of non-insul in dependent diabetes and obesity. (C) 1994 Wiley-Liss, Inc.