MEDIATION OF MOST ATYPICAL EFFECTS BY SPECIES HOMOLOGS OF THE BETA(3)-ADRENOCEPTOR

1 A wide panel of compounds acting on beta-adrenoceptors active either in mammalian heart or in rodent digestive tract and adipose tissues, were investigated for their effects on Chinese hamster ovary cells transfected with the human or murine beta(3)-adrenoceptor gene. 2 The beta(3)-agonists, bucindolol, CGP 12177A and pindolol exhibited the highest binding affinities; BRL 37344, LY 79771, ICI 201651 and SR 58611A presented high potencies in stimulating adenylyl cyclase; bupranolol appeared as the most efficient beta(3)-antagonist. 3 This pharmacological analysis further established that the beta(3)-adrenoceptor is the prototype of the adipose tissue atypical beta-adrenoceptor, since these receptors share a number of pharmacological properties which differ strikingly from those of beta(1)- and beta(2)-adrenoceptors: low affinities for conventional beta-adrenoceptor agonists and antagonists, high potencies for novel compounds active in adipose tissues, partial agonistic activites for several beta(1)/beta(2)-antagonists. 4 Although the pharmacological profiles of the human and murine beta(3)-receptor were very similar, some quantitative or even qualitative differences were observed for particular compounds such as propranolol, which exhibited weak and partial agonistic effects at the human beta(3)-receptors and antagonistic effects at the murine beta(3)-receptors. These differences may result from key amino-acid substitutions between the human and the murine beta(3)-receptor sequences, which may alter the binding site or signal processing. 5 Compounds active on atypical beta-sites of other tissues such as heart and digestive tract were also potent on the beta(3)-adrenoceptor expressed in Chinese hamster ovary cells, suggesting that this receptor mediates most of the atypical properties described in various tissues, and that differences in ligand effects may result from tissue-related specificities.