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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 287; no. 1; pp. 43 - 50
• Main Authors: McLeod, R L, Aslanian, R, del Prado, M, Duffy, R, Egan, R W, Kreutner, W, McQuade, R, Hey, J A
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.10.1998
• Subjects: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Capillary Permeability - drug effects; Electroencephalography - drug effects; Guinea Pigs; Histamine Agonists - pharmacology; Hypnotics and Sedatives - pharmacology; Imidazoles - pharmacology; Male; Migraine Disorders - drug therapy; Motor Activity - drug effects; Pentobarbital - pharmacology; Pyrrolidines - pharmacology; Receptors, Histamine H3 - drug effects; Reflex - drug effects; Sleep - drug effects
• ISSN: 0022-3565; 1521-0103

We studied the actions of Sch 50971, a novel histamine H 3 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 H 3 antagonist thioperamide (3.0 mg/kg i.v.). The 5-HT 1D agonist, sumatriptan (0.3 mg/kg i.v.), and the histamine H 3 agonist, ( R )-α-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 H 1 antagonist diphenhydramine and the H 3 receptor agonist ( R )-α-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 H 3 receptors that may act to ameliorate the sequelae of migraine headaches, where activation of histamine H 3 receptors may be beneficial. Sch 50971 also decreases motor activity and promotes EEG activity consistent with physiological sleep.