Clinical evaluation of a benzofuroquinolizine α 2 ‐adrenoceptor antagonist

The pharmacodynamics of MK‐912, a benzofuroquinolizine α 2 ‐adrenoceptor antagonist, were evaluated in healthy male volunteers. Eight subjects were treated with single oral doses of 0.1, 1.0, and 2.0 mg MK‐912 and with a placebo in a four‐period, double‐blind, balanced, crossover study. Hemodynamic effects were observed with the 2.0 mg dose of MK‐912 (peak increase from baseline in systolic and diastolic blood pressure ± SEM, 14.8/9.2 ± 2.9/2.1 mm Hg; peak increase in heart rate, 6.3 ± 2.1 beats/min; p < 0.05 versus placebo). Plasma concentrations of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG, a catecholamine metabolite) were increased 29% ± 7% and 40% ± 10% above baseline 2 hours after administration of 1.0 and 2.0 mg MK‐912, respectively ( p < 0.01 compared with placebo). A modest dose‐dependent reduction (5% to 10%) in fasting plasma glucose concentration was observed ½ to 1 hour after administration of 1.0 and 2.0 mg MK‐912 ( p < 0.05 compared with placebo), without significant change in plasma insulin values. MK‐912 was well tolerated, although it did have a mild anxiogenic effect. MK‐912 is a potent, orally active agent with a pharmacologic profile consistent with α 2 ‐adrenoceptor antagonism. Clinical Pharmacology and Therapeutics (1989) 46, 566–575; doi: 10.1038/clpt.1989.187