title: Awakening properties of newly discovered highly selective H₃ receptor antagonists in rats.
abstract: The objective of the present study was to compare the awakening effects of two newly discovered H₃ receptor antagonists (i.e. SAR110894 and SAR110068) with those of reference H₃ receptor ligands (i.e. ciproxifan, ABT-0239 and GSK189254) and classical psychostimulants (i.e. amphetamine and modafinil) by using EEG recording in rats during their light phase. Results showed that SAR110068 (10 and 30 mg/kg, p.o.) increased wakefulness and decreased slow wave sleep to a similar degree than ciproxifan (10 mg/kg, i.p.), ABT-0239 (10 mg/kg, p.o.) and GSK189254 (10 mg/kg, p.o.), while SAR110894 (3-30 mg/kg, p.o.) did not modify significantly any of the sleep/wakefulness parameters. Time-course analysis revealed that the awakening effects of GSK189254 lasted for about 1h, while ciproxifan, ABT-0239 and SAR110068 produced such effects for 3-4 h. The magnitude of the awakening effects of the psychostimulants, amphetamine (3 mg/kg, i.p.) and modafinil (300 mg/kg, i.p.), was dramatically higher than with the H₃ compounds, and they lasted for 5 and 6 h, respectively. However, unlike the H₃ receptor antagonists, both psychostimulants produced a strong increase in theta (θ) rhythm, which is indicative of CNS side effects, such as hyperactivity or abnormal excitation. In conclusion, this study provides further evidence to support the potential use of H₃ receptor antagonists in the treatment of vigilance and sleep-wake disorders such as narcolepsy.
authors.affiliation: Exploratory Unit, Sanofi, Chilly-Mazarin, France. guy.griebel@sanofi.com
authors.forename: Guy
authors.initials: G
authors.lastname: Griebel
authors.forename: Michel
authors.initials: M
authors.lastname: Decobert
authors.forename: Agnès
authors.initials: A
authors.lastname: Jacquet
authors.forename: Sandra
authors.initials: S
authors.lastname: Beeské
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D008297:Male; D000077408:Modafinil; D011714:Pyrans / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000502:physiology; D012890:Sleep / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects*
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D054828:Histamine H3 Antagonists; D011714:Pyrans; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C575741:tetrahydro-pyran-4-carboxylic acid (2-methyl-4-(2-methyl-(1,3')bipyrrolidinyl-1'-yl)phenyl)amide; D000661:Amphetamine; D000077408:Modafinil