Vol. 287, Issue 1, 43-50, October 1998

Sch 50971, an Orally Active Histamine H₃ Receptor Agonist, Inhibits Central Neurogenic Vascular Inflammation and Produces Sedation in the Guinea Pig

R. L. McLeod, R. Aslanian, M. del Prado, R. Duffy, R. W. Egan, W. Kreutner, R. McQuade and J. A. Hey

Schering-Plough Research Institute, Kenilworth, New Jersey

We studied the actions of Sch 50971, a novel histamine H₃ receptor agonist, in an experimental neurogenic model of migraine and characterized its sedative and respiratory actions. Sch 50971 (i.v. and p.o) inhibited plasma protein extravasation in the dura mater of guinea pigs after electrical stimulation of the trigeminal ganglia. The minimum effective 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, respectively. The effects of Sch 50971 (3.0 mg/kg i.v.) were blocked by the histamine H₃ antagonist thioperamide (3.0 mg/kg i.v.). The 5-HT_1D agonist, sumatriptan (0.3 mg/kg i.v.), and the histamine H₃ agonist, (R)--methylhistamine (0.3 mg/kg), also inhibited plasma extravasation by 40 and 46%. In sedation studies, Sch 50971 (1-100 mg/kg p.o.) potentiated pentobarbital-induced sleep. The ED_{40 min} for Sch 50971, the benzodiazepines triazolam and diazepam, the histamine H₁ antagonist diphenhydramine and the H₃ receptor agonist (R)--methylhistamine were 7.0, 0.5, 2.3, 14.1 and 23.4 mg/kg p.o., respectively. The sedative effects of oral Sch 50971 was blocked by thioperamide (10 µg i.c.v.). The sedative activity of Sch 50971 was also examined using EEG activity, locomotor activity and sleep. In conscious guinea pigs, Sch 50971 (10 mg/kg p.o.) depressed locomotor activity, increased total sleep time and produced EEG patterns consistent with physiological sleep. Sch 50971 decreased beta wave activity but had no effects on delta wave activity, theta activity or alpha wave activity. In contrast, triazolam (1.0 mg/kg p.o.) depressed delta and theta wave activity and produced large increases in alpha and beta wave activity. In conclusion, Sch 50971 is an orally active, potent and selective agonist of histamine H₃ receptors that may act to ameliorate the sequelae of migraine headaches, where activation of histamine H₃ receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity consistent with physiological sleep.