SCH-50971, AN ORALLY-ACTIVE HISTAMINE H-3 RECEPTOR AGONIST, INHIBITS CENTRAL NEUROGENIC VASCULAR INFLAMMATION AND PRODUCES SEDATION IN THE GUINEA-PIG

We studied the actions of Sch 50971, a novel histamine H-3 receptor ag onist, in an experimental neurogenic model of migraine and characteriz ed its sedative and respiratory actions. Sch 50971 (i.v. and p.o) inhi bited plasma protein extravasation in the dura mater of guinea pigs af ter electrical stimulation of the trigeminal ganglia. The minimum effe ctive doses of Sch 50971 were 3.0 mg/kg i.v. and 10 mg/kg p.o., which produced a 40% and 42% decrease in plasma protein extravasation, respe ctively. The effects of Sch 50971 (3.0 mg/kg i.v.) were blocked by the histamine H-3 antagonist thioperamide (3.0 mg/kg i.v.). The 5-MT1D ag onist, sumatriptan (0.3 mg/kg i.v.), and the histamine H-3 agonist, (R )-alpha-methylhistamine (0.3 mg/ kg), also inhibited plasma extravasat ion by 40 and 46%. In sedation studies, Sch 50971 (1-100 mg/kg p.o.) p otentiated pentobarbital-induced sleep. The ED40 min for Sch 50971, th e benzodiazepines triazolam and diazepam, the histamine H-1 antagonist diphenhydramine and the H-3 receptor agonist (R)alpha-methylhistamine were 7.0, 0.5, 2.3, 14.1 and 23.4 mg/kg p.o:, respectively. The sedat ive effects of oral Sch 50971 was blocked by thioperamide (10 mu g i.c .v.). The sedative activity of Sch 50971 was also examined using EEG a ctivity,locomotor activity and sleep. In conscious guinea pigs, Sch 50 971 (10 mg/kg p.o. depressed locomotor activity, increased total sleep time and produced EEG patterns consistent with physiological sleep. S ch 50971 decreased beta wave activity but had no effects on delta wave activity, theta activity or alpha wave activity. In contrast, triazol am (1.0 mg/kg p.o.) depressed delta and theta wave activity and produc ed large increases in alpha and beta wave activity. in conclusion, Sch 50971 is an orally active, potent and selective agonist of histamine H-3 receptors that may act to ameliorate the sequelae of migraine head aches, where activation of histamine H-3 receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity cons istent with-physiological sleep.