A Novel Potent and Selective Histamine H₃ Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor...

Histamine H₃ receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H₃ receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H₃ receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H₃ receptor agonist)-induced dipsogenia, and occupied the histamine H₃ receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H₃ receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H₃ receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H₃ receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H₃ receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H₃ receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H₃ receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.