A Novel Potent and Selective Histamine H₃ Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents

Abstract

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-1yl]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-αmethylhistamine (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.

Revisiting Preclinical Observations of Several Histamine H3 Receptor Antagonists/Inverse Agonists in Cognitive Impairment, Anxiety, Depression, and Sleep–Wake Cycle Disorder

“…Using the same mouse model, samelisant decreased NREM sleep and direct REM sleep onset episodes, showing an anti-cataplectic effect ( Nirogi et al, 2021a ). Another H3R antagonist/inverse agonist, namely, enerisant, was able to promote a waking effect by decreasing slow-wave sleep, however, at high doses ( Hino et al, 2020 ). Moreover, the H3R antagonist/inverse agonist SAR110068 produced wakefulness and decreased slow-wave and REM sleep to similar degrees as ciproxifan but for longer durations as shown by EEG ( Gao et al, 2013a ).…”

Histamine 3 receptor inverse agonist Samelisant (SUVN-G3031): Pharmacological characterization of an investigational agent for the treatment of cognitive disorders

“…Literature evidence suggests a demarcation between the doses that show procognitive and wake-promoting effects. Procognitive effects were observed at ~50% H3 receptor occupancy whereas greater than 70% occupancy is reported to be associated with wake-promoting effects (Hino et al, 2020; Jucaite et al, 2013).…”

Discovery of Novel Steroid-Based Histamine H3 Receptor Antagonists/Inverse Agonists

“…Among them, the naturally occurring steroid-based alkaloid, conessine, was demonstrated to bind to both rat and human H 3 receptors but not to other histamine receptors . Despite significant efforts to synthesize a chemically diverse variety of H 3 receptor-active ligands and successful phase I and phase II clinical trials (such as GSK-239512, ABT-288, AZD-5213, JNJ-31001074, MK-0249, PF-03654746, S-38093, Enerisant, and Samelisant), only pitolisant could reach the market in the indication of narcolepsy under the brand name of Wakix . (The human p K i data was included for all reference structures …”