Awakening properties of newly discovered highly selective H3 receptor antagonists in rats

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 1 h, 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.

► We compared the awakening effects of H3 antagonists with those of psychostimulants.
► The magnitude of awakening of the psychostimulants was higher than H3 compounds.
► The psychostimulants produced an increase in θ rhythm, indicative of side effects.
► H3 receptor antagonists may be effective against sleep-wake disorders.