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Evidence for a Secondary State of the Human 3-Adrenoceptor

Institute of Cell Signaling, Medical School, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom

There are three members of the -adrenoceptor family, all of which are primarily coupled to G_s proteins. Recent studies using the huge range of -ligands now available have given remarkable new insights into their pharmacology. 1-adrenoceptors exist in at least two active conformations, whereas 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 3-adrenoceptor stably expressed in Chinese hamster ovary cells. Several compounds described previously as -antagonists have agonist properties at the 3-adrenoceptor. Antagonist affinity measurements varied at the 3-adrenoceptor in a manner similar to those observed at human 1-adrenoceptors and unlike those seen at 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 [SR 59230A]) stimulated responses that were more resistant to antagonism. Alprenolol inhibited fenoterol-induced 3-adrenoceptor responses while acting as an agonist at higher concentrations. This is highly suggestive of two active conformational states of the 3-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 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 1-adrenoceptor. Both conformations are present in living cells and can be distinguished by their pharmacological characteristics. In this respect, the human 3-adrenoceptor seems similar to the human 1-adrenoceptor.

Address correspondence to: Dr. Jillian G. Baker, Institute of Cell Signaling, Queen's Medical Centre, Nottingham, NG7 2UH, United Kingdom. E-mail: jillian.baker{at}nottingham.ac.uk

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