Abstract
There are three members of the β-adrenoceptor family, all of which are primarily coupled to Gs proteins. Recent studies using the huge range of β-ligands now available have given remarkable new insights into their pharmacology. β1-adrenoceptors exist in at least two active conformations, whereas β2-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 β3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as β-antagonists have agonist properties at the β3-adrenoceptor. Antagonist affinity measurements varied at the β3-adrenoceptor in a manner similar to those observed at human β1-adrenoceptors and unlike those seen at β2-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 [SR 59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced β3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the β3-adrenoceptor. (S)-4-[2-Hydroxy-3-phenoxypropylaminoethoxy]-N-(2-methoxyethyl)phenoxyacetamide (ZD 7114) 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 β3-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 β1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human β3-adrenoceptor seems similar to the human β1-adrenoceptor.
- Received June 1, 2005.
- Accepted August 29, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|