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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics October 1998, 287 (1) 43-50;
R. L. McLeod
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R. Aslanian
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M. del Prado
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R. Duffy
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R. W. Egan
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W. Kreutner
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R. McQuade
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J. A. Hey
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Abstract

We studied the actions of Sch 50971, a novel histamine H3receptor 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-HT1D agonist, sumatriptan (0.3 mg/kg i.v.), and the histamine H3 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 ED40 min for Sch 50971, the benzodiazepines triazolam and diazepam, the histamine H1 antagonist diphenhydramine and the H3 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 H3receptors 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.

Footnotes

  • Send reprint requests to: John A. Hey, Ph.D, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539.

  • Abbreviations:
    CNS
    central nervous system
    i.c.v
    intracerebroventricular
    s.c
    subcutaneous
    SUMA
    sumatriptan
    NSAID
    nonsteroid anti-inflammatory drug
    DHE
    dihydroergotamine
    • Received May 2, 1998.
    • Accepted May 19, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 1
1 Oct 1998
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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 43-50;

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Research ArticleArticle

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
Journal of Pharmacology and Experimental Therapeutics October 1, 1998, 287 (1) 43-50;
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