Abstract

β₃-Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the β₃-adrenoceptor, was discovered much later than β₁- and β₂-adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the β₃-adrenoceptor a less-understood subtype. This article discusses three aspects of β₃-adrenoceptor pharmacology. First, the ligand-recognition profile of β₃-adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are β₃-sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being β₃-selective actually are not, including BRL 37,344 ((±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate) or SR 59,230 (3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate). Moreover, the binding pocket apparently differs between the human and rodent β₃-adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of β₃-adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of β₃-adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, β₃-adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the β₃-adrenoceptor as a novel pharmacological target.