Studies on the affinity and selectivity of denopamine (TA-064), a new cardiotonic agent, for .BETA.-adrenergic receptors.
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概要
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Denopamine is a new orally active cardiotonic agent. The present experiment was carried out to characterize the binding affinity and selectivity of this drug for β-adrenergic receptor subtypes. Binding studies were performed using <SUP>3</SUP>H-dihydroalprenolol as the radioligand. Binding affinities of denopamine and some β-agonists for rat heart membranes (K<SUB>iH</SUB>), which contain predominantly the β<SUB>1</SUB>-subtype, were in the order of isoproterenol (Iso, 14.1 nM)>prenalterol (158)>norepinephrine (Nor, 227)≥epinephrine (Epi, 248)>denopamine (545)≥ dobutamine (645)>procaterol (1440)>terbutaline (6420). In rat lung membranes (predominantly β<SUB>2</SUB>-subtype), the order of potency (K<SUB>iL</SUB>) was Iso (20.6 nM)>procaterol (70.2)>Epi (136)>prenalterol (412)>dobutamine (735)≥Nor (744)>denopamine (2205)>terbutaline (2500). The β<SUB>1</SUB>/β<SUB>2</SUB>-selectivity as judged from the K<SUB>iL</SUB>/K<SUB>iH</SUB> values was in the order of denopamine (4.1)>Nor (3.3)>prenalterol (2.6)> Iso (1.5)>dobutamine (1.1)>Epi (0.55)>terbutaline (0.39)> procaterol (0.05). Practolol, a β<SUB>1</SUB>-antagonist, showed a high β<SUB>1</SUB>-selectivity (K<SUB>iL</SUB>/K<SUB>iH</SUB>=15.3). In the presence of guanine nucleotide (GTP), the denopamine radioligand competition curve showed a rightward shift, and its Hill coefficient increased like other agonists, although the degree of the shift was less than that observed with full agonists such as Iso. These results essentially correspond with the pharmacological and biochemical properties of denopamine and confirm the β<SUB>1</SUB>-selectivity and the agonist property of this compound.
- 公益社団法人 日本薬理学会の論文
著者
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HARIGAYA Shoichi
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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Otsuka Minezo
Biological Research Laboratory Tanabe Seiyaku Co. Ltd.
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HARIGAYA Shoichi
Biological Research Laboratory : Organic Chemistry Research Laboratory : Tanabe Seiyaku Co., Ltd.
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NAKAJIMA Hiromichi
Biological and Chemical Reseach Labolatories, Tanabe Seiyaka Co., Ltd.
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NAGAO Taku
Biological Research Laboratories, Tauabe Seiyaku Co., Ltd.
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NAITO Kazuaki
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd.
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