A PRELIMINARY, CLINICAL PHARMACOLOGICAL ASSESSMENT OF L-659,066, A NOVEL ALPHA-2-ADRENOCEPTOR ANTAGONIST

1 The alpha2-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 alpha2-adrenoceptor antagonist activity with L-659,066 but with an approximately 9-fold lesser potency than yohimbine. 7 While L-659,066 has alpha2-adrenoceptor antagonist activity these, results suggest that it is unlikely to present a new therapeutic approach for improving insulin release.