Carazolol, an extremely potent β-adrenergic blocker: Binding to β-receptors in brain membranes

The binding of (±)-[³H]carazolol, a recently developed β-adrenergic antagonist of high potency, to rat cerebral cortical membranes is compared to the binding of (-)-[³H]dihydroalprenolol (³H-DHA). ³H-Carazolol binds saturably to cortical β-receptors with a K_D of 0.15 nM, a value approximately four times lower than that for ³H-DHA. Considering that ³H-carazolol was used as the racemic mixture and ³H-DHA as the (-)-isomer, an equivalent formulation of ³H-carazolol would be 8-10 times more potent than ³H-DHA. This increased affinity can be explained by the observed two fold greater association rate constant and a two fold lower dissociation rate constant. The drug displacement profile of ³H-carazolol binding is very similar to that of ³H-DHA. ³H-Carazolol has equal displacements constants when binding is performed in calf cerebral cortex (which contains mainly β₁ receptors) and calf cerebellum (which contains mainly β₂ receptors), indicating that ³H-carazolol binds with equal affinity to β₁ and β₂ receptors. The percent free drug (i.e. unbound to serum proteins) for both carazolol and propranolol in rabbit serum is approximately 10%. At physiologically equivalent doses of carazolol and propranolol in the rabbit, there is no detectable free β-blocking activity at 15, 30 or 60 min after intravenous injection of carazolol, although substantial propranolol activity is detected.