Beta(3)-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans

In the early 1980s, an "atypical" beta-adrenergic receptor was discovered a nd subsequently called the beta(3)-adrenoceptor (beta (3)-AR). Agonists of the beta (3)-AR were observed to simultaneously increase lipolysis, fat oxi dation, energy expenditure and insulin action leading to the belief that th is receptor might serve as an attractive target for the treatment of diabet es and obesity. In vivo studies lent credence to this postulate with the fi nding that stimulation of this receptor by selective agonists lead to glyce mic improvements and weight loss in rodent models of diabetes and obesity. This lead to intensive research efforts directed at developing beta (3)-AR selective agonists for the treatment of type 2 diabetes and obesity in huma ns. Unfortunately, endeavour been largely unsuccessful to date. Major obsta cles have included the pharmacological differences between the rodent and h uman beta (3)-AR, the lack of selectivity of previous compounds for the bet a (3)-AR over beta (1)-/beta (2)-ARs, and unsatisfactory oral bioavailabili ty and pharmacokinetic properties. Cloning of the human beta (3)-AR has all owed for the development of novel compounds targeted specifically at the hu man receptor. Encouraging data has emerged from clinical studies wherein CL 316,243, a highly selective, albeit rodent specific beta (3)-AR agonist was observed to increase lipolysis, fat oxidation and insulin action in humans . More recently, beta (3)-AR agonists directed at the human receptor are sh owing promising results in their ability to increase energy expenditure in humans following a single dose. However, they do not appear to be able to s ustain their effects when administered chronically. Further clinical testin g will be necessary, using compounds with improved oral bioavailability and potency, to help assess the physiology of the beta (3)-AR in humans and it s attractiveness as a potential therapeutic for the treatment of type 2 dia betes and obesity.