Human beta 1- and beta 2-adrenergic receptor binding and mediated accumulation of cAMP in transfected Chinese hamster ovary cells. Profile of nebivolol and known beta-adrenergic blockers.
The interaction of nebivolol and its SRRR and RSSS enantiomers, and of known beta-adrenergic blockers, with human beta 1- and beta 2-adrenergic receptors expressed separately in Chinese hamster ovary cells in culture (CHO-Hu beta 1 and CHO-Hu beta 2), was investigated. We studied [3H]CGP-12177 binding to the intact cells and the accumulation of cAMP induced by isoproterenol. Each of the receptor subtypes displayed saturable [3H]CGP-12177 binding on intact cells with sub-nanomolar affinity. The density of beta 1- and beta 2-adrenergic receptor sites was 1.1 x 10(6) receptor binding sites per CHO-Hu beta 1 cell and 0.2 x 10(6) receptor binding sites per CHO-Hu beta 2 cell, respectively. The beta-adrenergic antagonists CGP 20712-A, ICI 118-551 and propranolol showed the same binding properties as beta-adrenergic receptors in previously described tissues or cells. The potencies of these compounds in inhibiting beta-adrenergic receptor mediated accumulation of cAMP corresponded well with their binding affinities. d-Nebivolol (SRRR) and nebivolol showed combined high affinity and selectivity for inhibition of beta 1-adrenergic receptor coupled accumulation of cAMP in CHO-Hu beta 1 cells (0.41 and 0.42 nM for d-nebivolol and nebivolol, respectively). l-Nebivolol (RSSS) was 1460 times less potent than d-nebivolol in CHO-Hu beta 1 cells. The binding affinities of d-nebivolol and nebivolol for human beta 1-adrenergic binding sites correlated well with their potencies in inhibiting beta 1-adrenergic receptor coupled accumulation of cAMP. CHO cells transfected with human beta 1- and beta 2-adrenergic receptors are a valid model system for studying the interaction of compounds with human beta-adrenergic receptors.
Pauwels
P J
PJ
Department of Biochemical Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Van Gompel
P
P
Leysen
J E
JE
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism*; D004983:Ethanolamines / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008954:Models, Biological; D000068577:Nebivolol; D011412:Propanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013237:Stereoisomerism; D014162:Transfection
D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D007093:Imidazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000068577:Nebivolol; C026777:ICI 118551; D011433:Propranolol; C049763:CGP 20712A; D000242:Cyclic AMP; D007545:Isoproterenol; C033394:CGP 12177