Evidence for a secondary state of the human β3-adrenoceptor

There are three members of the beta-adrenoceptor family, all of which are primarily coupled to G(S) proteins. Recent studies using the huge range of beta-ligands now available have given remarkable new insights into their pharmacology. beta 1-adrenoceptors exist in at least two active conformations, whereas beta 2-adrenoceptors are able to induce signaling via different agonist-induced receptor conformational states, and their affinity for antagonists can be altered by highly efficacious agonists. This study therefore examined the pharmacology of the human beta 3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as beta-antagonists have agonist properties at the beta 3-adrenoceptor. Antagonist affinity measurements varied at the beta 3-adrenoceptor in a manner similar to those observed at human beta 1-adrenoceptors and unlike those seen at beta 2-adrenoceptors. Some ligands ( e. g., fenoterol and cimaterol) were more readily inhibited by all antagonists, whereas other ligands [ e. g., alprenolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl] amino](2S)-2-propanol hydrochloride [SR59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced beta 3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the beta 3-adrenoceptor. (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide (ZD7114) stimulated a two-component response, of which the first component was more readily antagonized than the second. Taken together, these experiments suggest that the human beta 3-adrenoceptor exists in at least two different agonist conformations with a similar high- and low-affinity pharmacology analogous to, if not as pronounced as, the beta 1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human beta 3-adrenoceptor seems similar to the human beta 1-adrenoceptor.