title: Clinical evaluation of a benzofuroquinolizine alpha 2-adrenoceptor antagonist.
abstract: The pharmacodynamics of MK-912, a benzofuroquinolizine alpha-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 less than 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 less than 0.01 compared with placebo). A modest dose-dependent reduction (5% to 10%) in fasting plasma glucose concentration was observed 1/2 to 1 hour after administration of 1.0 and 2.0 mg MK-912 (p less than 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 alpha 2-adrenoceptor antagonism.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
authors.forename: B J
authors.initials: BJ
authors.lastname: Gertz
authors.forename: P H
authors.initials: PH
authors.lastname: Vlasses
authors.forename: M L
authors.initials: ML
authors.lastname: Rocci
authors.forename: L D
authors.initials: LD
authors.lastname: Coker
authors.forename: V
authors.initials: V
authors.lastname: Williams
authors.forename: T D
authors.initials: TD
authors.lastname: Bjornsson
authors.forename: K H
authors.initials: KH
authors.lastname: Jones
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D000339:Affect / Q000187:drug effects; D000704:Analysis of Variance; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000097:blood; D011807:Quinolizines / Q000494:pharmacology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D001786:Blood Glucose; D007328:Insulin; D011807:Quinolizines; C054290:L 657743; D008734:Methoxyhydroxyphenylglycol