Arch J R, Wilson S
SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
Int J Obes Relat Metab Disord. 1996 Mar;20(3):191-9.
beta 3-Adrenoceptor (beta 3-AR) agonists were first identified more than twelve years ago and were found to be remarkably effective in animal models of obesity and Type II (non-insulin dependent) diabetes. Those that have been taken forward to clinical studies have not, however, proved so effective in humans: they have either been of limited efficacy, or their activities have been accompanied by significant side-effects. Reasons for the failure of some beta 3-AR agonists in humans have included a poor pharmacokinetic profile and, possibly, a failure of prodrugs to be metabolised to selective beta 3-AR agonists. A more fundamental problem, however, is that the human and rat beta 3-AR differ pharmacologically, and those compounds that have been evaluated in humans have much lower efficacy at the human than the rat receptor. This problem may be compounded by there being a low number of beta 3-AR relative to beta 1-AR and beta 2-AR in those tissues that mediated thermogenesis in humans, so that low efficacy compounds tend to exhibit mainly beta 1-AR or beta 2-AR-, rather than beta 3-AR-mediated effects, despite their having selective affinity for human beta 3-AR. Nevertheless, studies using CGP 12177, which is an agonist at beta 3-AR but an antagonist at beta 1-AR and beta 2-AR, demonstrate that functional beta 3-AR are present in human adipose tissue. Moreover, the association of a polymorphism in the human beta 3-AR with obesity and diabetes demonstrates that this receptor is relevant to these diseases in humans. Thus the true potential of beta 3-AR agonists in humans can only be evaluated when a compound with good selectivity and efficacy at the human beta 3-AR, coupled with a long duration of action in vivo, has been identified.
β3肾上腺素能受体（β3-AR）激动剂早在十二多年前就被首次发现，并且发现在肥胖和II型（非胰岛素依赖型）糖尿病动物模型中具有显著疗效。然而，那些进入临床研究阶段的β3-AR激动剂在人体中并未显示出如此显著的效果：它们要么疗效有限，要么其作用伴随着明显的副作用。一些β3-AR激动剂在人体中失败的原因包括药代动力学特性不佳，以及前体药物可能无法代谢为选择性β3-AR激动剂。然而，一个更根本的问题是，人类和大鼠的β3-AR在药理学上存在差异，在人体中评估的那些化合物对人类β3-AR的效力远低于对大鼠受体的效力。相对于介导人体产热的组织中β1-AR和β2-AR而言，β3-AR数量较少，这可能会使问题更加复杂，以至于效力较低的化合物尽管对人类β3-AR具有选择性亲和力，但往往主要表现出β1-AR或β2-AR介导的效应，而非β3-AR介导的效应。尽管如此，使用CGP 12177（一种β3-AR激动剂，但对β1-AR和β2-AR为拮抗剂）进行的研究表明，功能性β3-AR存在于人体脂肪组织中。此外，人类β3-AR基因多态性与肥胖症和糖尿病的关联表明，该受体与人类的这些疾病相关。因此，只有当确定了一种对人类β3-AR具有良好选择性和效力、并在体内具有长效作用的化合物时，才能评估β3-AR激动剂在人体中的真正潜力。
