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Antidiabetic and antiobesity effects of a highly selective β 3 ‐adrenoceptor agonist (CL 316,243)
Author(s) -
Largis Elwood E.,
Burns Michael G.,
Muenkel Helen A.,
Dolan Jo Alene,
Claus Thomas H.
Publication year - 1994
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430320203
Subject(s) - endocrinology , medicine , agonist , chemistry , adipose tissue , insulin resistance , insulin , thermogenesis , triglyceride , receptor , in vivo , weight gain , brown adipose tissue , cholesterol , biology , body weight , microbiology and biotechnology
A third β‐adrenoceptor subtype has been cloned form the rat, mouse, and human genomes. The presence of these receptors primarily on adipose tissue has raised the possibility that β 3 ‐adrenoceptor selective agonists may be useful antiobesity agents. CL 316,243 is a highly selective β 3 ‐agonist; it has a <30,000 to 1 β 3 ‐to‐β 1 ‐adrenoceptor selectivity ratio and a 10,000 to 1 β 3 ‐to‐β 2 ‐adrenoceptor selectivity ratio in in vitro functional assays. In vivo, animals were treated with CL 314,698, a diester prodrug of CL 316,243, which 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 also improved both glucose and insulin tolerance in obese mice, suggesting that it decreased insulin resistance. CL 314,698 also prevented further weight gain, without affecting food consumption, in rats previously made obese by feeding a high fat diet. The compound reduced plasma insulin and triglyceride levels, and reduced fat pad weights, while having no effect on plasma glucose, cholesterol, thyroxine, or T 3 levels or on skeletal muscle weight. Decreased weight gain without decreased food consumption suggested that CL 316,243 stimulated thermogenesis. Treatment of obese mice for 3 weeks with CL 316,243 increased thermogenesis by 45% as measured by indirect calorimetry. Thus, CL 316,243 is a potent, β 3 ‐adrenoceptor selective agonist with thermogenic, antidiabetic, and antiobesity properties in several models of non‐insulin dependent diabetes and obesity.