RT Journal Article
SR Electronic
T1 A Novel Potent and Selective Histamine H3 Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, Wake-Promoting and Pro-cognitive Effects in Rodents
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000185
DO 10.1124/jpet.120.000185
A1 Hino, Noriko
A1 Marumo, Toshiyuki
A1 Kotani, Makiko
A1 Shimazaki, Toshiharu
A1 Kaku-Fukumoto, Ayaka
A1 Hikichi, Hirohiko
A1 Karasawa, Jun-ichi
A1 Tomishima, Yasumitsu
A1 Komiyama, Hiroko
A1 Tatsuda, Emi
A1 Nozawa, Dai
A1 Nakamura, Toshio
A1 Chaki, Shigeyuki
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/08/29/jpet.120.000185.abstract
AB 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 pro-cognitive 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 receptor 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 pro-cognition 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 pro-cognitive 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.