Pharmacology of ASL-8052, a Novel β-Adrenergic Receptor Antagonist with an Ultrashort Duration of Action

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Abstract
Summary ASL-8052, a novel β-adrenergic receptor antagonist, was studied in isolated guinea pig cardiac and tracheal tissues, in isolated frog sciatic nerves, and in anesthetized dogs. The compound was a moderately potent β-adrenoceptor antagonist in right atria (pA2 6.96) but was much less active in tracheal tissues (pA2 5.33), indicating cardioselective properties. ASL-8052 possessed a small degree of intrinsic sympathomimetic action in isolated guinea pig right atria and caused direct cardiac depression only at concentrations 1,000-fold higher than its cardiac pA2. Significant local anesthetic action in frog sciatic nerve occurred at extremely high concentrations of ASL-8052 (>0.1 M). In anesthetized dogs, ASL-8052 produced steady-state levels of β-blockade within 10 min during a 3-h intravenous infusion. In contrast, propranolol produced increasing levels of blockade throughout most of the infusion period. Recovery from β-blockade occurred rapidly following termination of ASL-8052 infusion (80% recovery in approximately 12 min), whereas very little recovery occurred following cessation of propranolol infusion. Intravenous infusion of ASL-8052 produced dose-dependent blockade of cardiac responses to isoproterenol but only minimally decreased hind limb vascular responses to isoproterenol. The resuts indicate that ASL-8052 is a novel cardioselective β-blocker with an ultrashort duration of action.

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