A preliminary, clinical pharmacological assessment of L-659,066, a novel alpha 2-adrenoceptor antagonist.

1. The alpha 2-adrenoceptor antagonist activity of L-659,066 has been investigated in studies of healthy normotensive males to whom doses of up to 8 mg were administered by short intravenous infusion. 2. L-659,066 had no effect on basal levels of glucose or insulin and no significant effect on the plasma glucose and plasma insulin time profiles following an intravenous glucose load. 3. There was a non-significant trend for plasma noradrenaline concentrations to be higher after L-659,066. 4. L-659,066 had no significant effects on mood changes or on physical symptom scores. 5. There were no significant effects on supine blood pressure but there were consistent increases in heart rate both supine (non-significant) and erect (P < 0.01). 6. Ex vivo platelet aggregation studies confirmed alpha 2-adrenoceptor antagonist activity with L-659,066 but with an approximately 9-fold lesser potency than yohimbine. 7. While L-659,066 has alpha 2-adrenoceptor antagonist activity these results suggest that it is unlikely to present a new therapeutic approach for improving insulin release.