ADVANCES IN PHARMACOTHERAPY FOR OBESITY

Anorectic drugs are increasingly being used in obesity to induce and/o r maintain weight loss. We have focused on the development of metaboli c enhancers. These compounds increase energy expenditure, which is imp ortant because weight loss is associated with metabolic re-adjustment to reduce energy output. Thus, metabolic enhancers ensure that energy expenditure is maintained when food intake is reduced. beta(3)-adrenoc eptor agonists are thermogenic agents that increase energy output by s timulating heat generation. Early selective beta(3)-agonists were effe ctive in producing weight loss in obese rats, but were largely ineffec tive in humans. In addition, many interacted with other types of beta receptor to produce side-effects. The development of a Chinese hamster ovary cell (CHO) transfection system, using the human beta(3)-adrenoc eptor gene, resulted in potential new selective human beta(3)-agonists being identified. However, the in vitro activity of these agents does not necessarily reflect their action in vivo, due to the presence of other receptor types and G proteins in the target cells, and interacti ons between them. The characterization of a selective beta(3)-antagoni st, SR59230A, has allowed us to examine beta(3)-agonist activity in di fferent experimental systems. The CHO transfection system has been use d to show that SR59230A is effective in blocking agonist activity agai nst both the rat adrenoceptor, and three human beta(3)-receptor isofor ms. In addition, SR59230A shows competitive inhibition of agonist acti vity in both rat and human model systems. This antagonist may therefor e provide a pharmacological tool for the functional study of by newly identified beta(3)-receptor agonists.