Stereospecific binding of timolol, a beta-adrenergic blocking agent.

The beta-adrenergic blocking agent, timolol, appears to be bound to stereospecific as well as nonspecific sites in the particulate fraction (8500g pellet) of the heart, lungs, and brain, whereas the d-isomer of timolol was bound to nonspecific sites only. Timolol disappeared from the particulate fraction at a slower rate than did its optical isomer. At 1 hr after a 0.1-mg/kg dose, the concentration of the l-form in the lung was 1.8 times that of the d-isomer and at 3 and 4 hr the difference was at least 33-fold. The concentration of 14C-timolol in the particulate fraction of rat tissues was inhibited by iv administered timolol and by the l-isomer of propanolol, but not by their corresponding d-forms. Competition for binding sites was dose dependent. Pretreatment with timolol at 0.1 and 5.0 mg/kg reduced the binding of 14C-timolol (dose, 0.1 mg/kg) to lung tissue by 41% and 86%, respectively. In the heart and lung tissue of rats, racemic timolol, propranolol, bunolol, and bunitrolol were approximately equally effective in competing for the binding sites of 14C-timolol. Practolol and sotalol and the beta 2-selective agent butoxamine did not significantly inhibit the binding of 14C-timolol. Similar competition was also observed in the whole brain of rats. This report suggests that the stereospecific binding of timolol may be related to the beta-adrenoreceptor process.