Molecular pharmacology of beta adrenoreceptors in multiple disease states

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Obesity is a major and increasing health concern for almost half the adult population, and is associated with serious medical conditions including diabetes and heart disease. Changes in behaviour such as increasing physical activity and eating less high-calorie food help many people reduce their body weight, however many others have a genetic predisposition to become overweight and behavioural measures are ineffective. Although anti-obesity drugs should be a valuable adjunct to lifestyle changes, the currently available appetite suppressants are not ideal. Our work involves studying particular cell-surface proteins (receptors) which normally respond to hormones such as adrenaline. The beta(3)-adrenergic receptor is known to mediate the breakdown of fats and increased heat production in adipose tissue and possibly muscle. Administration of beta(3)-selective drugs to obese mice promotes weight loss and a reduction of diabetic symptoms, and a number of drugs targetting the human beta(3)-adrenergic receptor are being developed by pharmaceutical companies. We are trying to understand more about the properties of this receptor, as this information will assist in designing drugs which are more selective and more potent. Sometimes drugs act at more than one receptor, and there is evidence that this may be the case for two drugs called CGP 12177 and BRL 37344 which stimulate the beta(3)-adrenergic receptor. The second major aim of our project is to find out whether these drugs act at a novel receptor which is related to the beta(3)-adrenergic receptor and also mediates energy expenditure and heat production in adipose tissue and skeletal muscle. The discovery of a new receptor would provide additional scope for the development of effective anti-obesity treatments.