Studies on the Affinity and Selectivity of Denopamine (TA-064), a New Cardiotonic Agent, for β-Adrenergic Receptorst

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Abstract
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 3H-dihydroalprenolol as the radioligand. Binding affinities of denopamine and some β-agonists for rat heart membranes (KiH), which contain predominantly the β1-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 β2-subtype), the order of potency (KiL) was Iso (20.6 nM)>procaterol (70.2)>Epi (136)>prenalterol (412)>dobutamine (735)≥Nor (744)>denopamine (2205)>terbutaline (2500). The β1/β2-selectivity as judged from the KiL/KiH 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 β1-antagonist, showed a high β1-selectivity (KiL/KiH=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 β1-selectivity and the agonist property of this compound.

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