| Abstract: | In several species of obese animals, a group of phenethanolamine β-agonists stimulates lipolysis and thermogenesis, resulting in the loss of body fat and weight. Brown adipose tissue is considered to be the major target tissue for the antiobesity activity of these compounds. Independent of this antiobesity activity, some of these compounds are also antidiabetic and increase muscle mass. Based on the pharmacological profile of these com-pounds, a npeceptor was proposed and character-ized in mouse, rat, and humans. The 133-receptor in brown adipose tissue has been suggested to mediate the antiobesity activity of these 13-agonists. Whether this receptor is responsible for the antidiabetic activ-ity and whether there is a linkage between the antiobesity/antidiabetic activity and the nutrient par-titioning activity is not clear. Clinical trials with these mixed 13-agonists showed marginal antiobesity effects when caloric intake of subjects was restricted. Insulin sensitivity was also improved in some of the trials designed to test the antidiabetic activity of these compounds. Side effects included tachycardia and tremor. To eliminate these side effects, a second generation of compounds was selected for its agonist activity on rat D3-receptors. Clinical trials with these compounds have shown lit-tle increase of energy expenditure even at high doses. Successful development of an antiohesity and antidi-abetic drug from this class of compounds will require the elucidation of the physiological role of the human 133-receptor and the regulatory mecha-nism between fuel efficiency and feeding behavior. |
