Historical setting In the latter part of the 1970s and the early 1980s three pharmaceutical companies were attempting to design drugs that would retain the thermogenic and antiobesity activity in rodents of nonselective sympathomimetic agents, while lacking the undesirable effects elicited by such agents, in particular increased heart rate and tremor. These companies were Lilly [Yen et al. 1984] Beecham Pharmaceuticals (for which this author worked)[Arch et al. 1984b], and Hoffman-La-Roche [Meier et al. 1984]. Others revealed their interest a little later [Holloway et al. 1991]. From this work, Beecham Pharmaceuticals identified compounds that activated an ‘atypical’β-adrenoceptor in rodent brown and white adipocytes [Arch et al. 1984a]. From 1974 Zaagsma and colleagues had gathered evidence that the rat white adipocyte β-adrenoceptor was atypical but they had used only antagonists [Harms et al. 1974]. Antagonists mostly display low potency at the atypical β-adrenoceptor compared with β1-and β2-adrenoceptors. Even before Zaagsma’s work, Furchgott had reviewed antagonist data that showed that the β-adrenoceptor in various parts of the gut is atypical [Furchgott, 1972]. Tan and Curtis-Prior suggested in 1983 that the adipocyte receptor should be called the β3-adrenoceptor, but it was not until 1989 that I argued strongly for the use of this name to describe the atypical adipocyte β-adrenoceptor [Arch, 1989]. Soon afterwards, the human β3-adrenoceptor was cloned [Emorine et al. 1989] and subsequent work showed that the rodent β3-adrenoceptor is identical to the atypical β-adrenoceptor found in both adipocytes and the gut. It also became clear that the β3-adrenoceptor is primarily responsible for thermogenesis (increased energy expenditure) and fat loss in response to sympathetic stimulation in obese rodents. Fuller versions of this sequence of events have been published previously [Arch, 2008; Arch and Kaumann, 1993].

Some words of caution are needed for those who have not followed events over the years: the terms ‘atypical β-adrenoceptor’and a ‘third β-adrenoceptor’[Kaumann, 1989] have been used to describe a β-adrenoceptor (or β-adrenoceptors) that is not the β3-adrenoceptor. In particular, there is a form of the β1-adrenoceptor that has atypical pharmacology and in some respects is similar to that of the β3-adrenoceptor. For example, both receptors are stimulated by certain ‘nonconventional β-blockers’, such as ()-pindolol, at concentrations much higher than those that block β1-and β2-adrenoceptors, and both receptors have low affinity for conventional βblockers. One difference, however, is that the original (arylethanolamine) β3-adrenoceptor agonists have low potency at the atypical β1-adrenoceptor [Brahmadevara et al. 2003; Arch, 2002; Brawley et al. 2000]. After being called the ‘third heart β-adrenoceptor’[Kaumann, 1989], the atypical β1-adrenoceptor was for a few years known as the β4-adrenoceptor [Kaumann, 1997] but studies in knockout mice demonstrated that its pharmacological detection depended on the presence of the β1-but not the β3-adrenoceptor gene [Kaumann et al. 2001, 1998; Cohen et al. 2000; Konkar et al. 2000]. Even though it is not a genetically distinct β-adrenoceptor, this ‘low affinity β1-adrenoceptor,’as it is now usually called, could conceivably offer a target for drugs, especially for the treatment of cardiovascular disease [Arch, 2004].