Identification of potent agonists acting at an endogenous atypical β3-adrenoceptor state that modulate lipolysis in rodent fat cells

Small molecules interacting with aminergic G-protein coupled receptors represent a number of very successful drugs. G-protein coupled receptors continue to be a significant group of targets for pharmaceutical intervention, and modifying their activity through small molecules is a major focus of drug development. Previously, these small molecules could be easily fit in models, as agonists, partial agonists or antagonists. More recently, however, these lines have been blurred as it is increasingly recognized that ligands can interact with receptors in various ways. Analysis of beta-adrenoceptors has revealed that several sites or states exist for the individual receptors. The putative atypical β4-adrenoceptor identified on heart and adipose tissue is now recognized as a unique β1-adrenoceptor state. Similarly, a unique β3-adrenoceptor state has been identified using the aryloxypropanolamine CGP-12,177 and cloned receptor systems. Here we expand upon these observations, by describing an atypical state of the β3-adrenoceptor that exists endogenously in adipose tissue. Furthermore, we describe novel arylethanolamine ligands that interact with this atypical state of the β3-adrenoceptor with high affinity and provide additional tools to investigate the atypical β3-adrenoceptor state to determine whether it can be influenced for therapeutic purposes.