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更新于：2026-01-10

Histamine H3 receptor agonists(Freie Universität Berlin)

更新于：2026-01-10

概要

概要

基本信息

药物类型

小分子化药

别名-

靶点

H3 receptor

作用方式

激动剂

作用机制

H3 receptor激动剂(组胺H3受体激动剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Freie Universität Berlin

在研机构

Freie Universität Berlin

非在研机构-

权益机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 Histamine H3 receptor agonists(Freie Universität Berlin) 相关的临床结果

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100 项与 Histamine H3 receptor agonists(Freie Universität Berlin) 相关的转化医学

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100 项与 Histamine H3 receptor agonists(Freie Universität Berlin) 相关的专利（医药）

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153

项与 Histamine H3 receptor agonists(Freie Universität Berlin) 相关的文献（医药）

2026-01-01·EUROPEAN JOURNAL OF PHARMACOLOGY

Histamine N-methyltransferase inhibition as a novel therapeutic strategy for idiopathic hypersomnia

Article

作者: Nakamura, Tadaho ; Fujiya, Motoki ; Ebina, Ren ; Watanabe, Masahiko ; Hirano, Kyosuke ; Mimura, Toshimasa ; Mochizuki, Takatoshi ; Nishibe, Ayaka ; Naganuma, Fumito ; Miyoshi, Chika ; Funato, Hiromasa ; Zhu, Ruoyu ; Yanagisawa, Masashi ; Girgin, Birkan ; Vetrivelan, Ramalingam ; Yoshikawa, Takeo

Idiopathic hypersomnia (IH) is a sleep disorder characterised by excessive daytime sleepiness despite adequate night-time sleep. Although current treatments, including low-sodium oxybate and modafinil, are readily available for IH, they are associated with side effects such as drug dependence and abuse. Histamine, a key neurotransmitter, plays a critical role in promoting wakefulness and reducing the risk of drug dependence. Clinical studies have found reduced histamine levels in the cerebrospinal fluid of patients with hypersomnia, suggesting that enhanced histaminergic neurotransmission could alleviate IH symptoms. In our recent study, we demonstrated that the pharmacological inhibition of histamine N-methyltransferase (HNMT), the enzyme responsible for histamine degradation, significantly increased brain histamine levels and improved hypersomnolence and sleep attacks in a mouse model of narcolepsy. Based on these findings, we hypothesised that HNMT inhibitors could serve as novel therapeutic agents for IH treatment. In this study, we examined the effects of metoprine, a potent HNMT inhibitor, on sleep-wake behaviour in Sik3^Sleepy mutant mice, a mouse model of IH. Our results show that metoprine significantly increased brain histamine levels without altering dopamine, norepinephrine, or serotonin levels. Sleep analysis revealed that metoprine markedly promoted wakefulness and prolonged sleep latency, likely through the activation of the histamine receptor H1. Furthermore, the wake-up promoting effect of metoprine was more pronounced than that of other agents, including a histamine receptor H3 inverse agonist and an orexin receptor agonist. These findings suggest that the pharmacological inhibition of HNMT represents a promising therapeutic strategy for IH.

2024-04-01·European journal of pharmacology

Pharmacological characterization of seven human histamine H3 receptor isoforms

Article

作者: Vischer, Henry F ; Gao, Meichun ; Leurs, Rob ; Dekker, Mabel E

The histamine H₃ receptor (H₃R) regulates as a presynaptic G protein-coupled receptor the release of histamine and other neurotransmitters in the brain, and is consequently a potential therapeutic target for neuronal disorders. The human H₃R encodes for seven splice variants that vary in the length of intracellular loop 3 and/or the C-terminal tail but are all able to induce heterotrimeric G_i protein signaling. The last two decades H₃R drug discovery and lead optimization has been exclusively focused on the 445 amino acids-long reference isoform H₃R-445. In this study, we pharmacologically characterized for the first time all seven H₃R isoforms by determining their binding affinities for reference histamine H₃ receptor agonists and inverse agonists. The H₃R-453, H₃R-415, and H₃R-413 isoforms display similar binding affinities for all ligands as the H₃R-445. However, increased agonist binding affinities were observed for the three shorter isoforms H₃R-329, H₃R-365, and H₃R-373, whereas inverse agonists such as the approved anti-narcolepsy drug pitolisant (Wakix®) displayed significantly decreased binding affinities for the latter two isoforms. This opposite change in binding affinity of agonist versus inverse agonists on H₃R-365 and H₃R-373 is associated with their higher constitutive activity in a cAMP biosensor assay as compared to the other five isoforms. The observed differences in pharmacology between longer and shorter H₃R isoforms should be considered in future drug discovery programs.

2023-04-01·The Lancet. Neurology

Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial

Article

作者: Isabelle Lecomte ; Christian Caussé ; Jean Charles Schwartz ; Patricia Franco ; Jeanne Marie Lecomte ; Gert Jan Lammers ; Giuseppe Plazzi ; Michel Lecendreux ; Philippe Lehert ; Yves Dauvilliers ; Mikhail Poluektov

BACKGROUND:

Narcolepsy is a life-long disorder characterised by excessive daytime sleepiness and cataplexy, often arising in childhood or adolescence. Pitolisant, a selective histamine H3 receptor inverse agonist, has been approved in Europe and USA for adults with narcolepsy with or without cataplexy, with a favourable safety profile. This phase 3 study aimed to assess the safety and efficacy of pitolisant in children with narcolepsy with or without cataplexy.

METHODS:

For this double-blind, randomised, placebo-controlled, multisite study, we recruited patients aged 6-17 years with narcolepsy with or without cataplexy in 11 sleep centres in five countries (Italy, France, Netherlands, Russia, and Finland). Participants were required to have a Pediatric Daytime Sleepiness Scale score of 15 or greater and to have not received psychostimulants for at least 14 days before enrolment; participants who needed anticataplectics (including sodium oxybate) were required to have been on a stable dose for at least 1 month. Participants were randomly assigned to treatment with pitolisant or placebo in a 2:1 ratio at the end of screening. Randomisation was stratified by study centre and treatment was allocated using an interactive web response system. After a 4-week screening period including a 2-week baseline period, patients entered in a 4-week individual up-titration scheme from 5 mg a day to a maximum of 40 mg a day of pitolisant or placebo; treatment was administered at a stable dose for 4 weeks, followed by a 1-week placebo period. For the primary analysis, we assessed pitolisant versus placebo using change in the Ullanlinna Narcolepsy Scale (UNS) total score from baseline to the end of double-blind period in the full analysis set, defined as all randomly allocated patients who received at least one dose of treatment and who had at least one baseline UNS value. A decrease in the UNS total score reflects a reduction in both excessive daytime sleepiness and cataplexy. All adverse events were assessed in the safety population, defined as all participants who took at least one dose of study medication. An open-label follow-up is ongoing. This study is registered at ClinicalTrials.gov, NCT02611687.

FINDINGS:

Between June 6, 2016, and April 3, 2021, we screened 115 participants and 110 were randomly assigned (mean age 12·9 [SD 3·0] years, 61 [55%] male, and 90 [82%] with cataplexy; 72 assigned to pitolisant and 38 to placebo); 107 (70 receiving pitolisant and 37 receiving placebo) completed the double-blind period. The mean adjusted difference in UNS total score from baseline to the end of the double-blind period was -6·3 (SE 1·1) in the pitolisant group and -2·6 (1·4) in the placebo group (least squares mean difference -3·7; 95% CI -6·4 to -1·0, p=0·007). Treatment-emergent adverse events were reported in 22 (31%) of 72 patients in the pitolisant group and 13 (34%) of 38 patients in the placebo group. The most frequently reported adverse events (affecting ≥5% of patients) in either group were headache (14 [19%] in the pitolisant group and three [8%] in the placebo group) and insomnia (five [7%] in the pitolisant group and one [3%] in the placebo group).

INTERPRETATION:

Pitolisant treatment resulted in an improvement in narcolepsy symptoms in children, although the UNS was not validated for use in children with narcolepsy when our study began. The safety profile was similar to that reported in adults but further studies are needed to confirm long-term safety.

FUNDING:

Bioprojet.

项与 Histamine H3 receptor agonists(Freie Universität Berlin) 相关的新闻（医药）

2025-06-26

·FierceBiotech

Alto misses primary efficacy endpoint in phase 2 depression trial

Alto Neuroscience expects to decide the next steps for ALTO-203 once it finishes the complete analysis of the dataset. \n Alto Neuroscience’s phase 2 depression trial has missed its primary efficacy endpoint, as patients on the drug candidate fared no better on a measure of alertness and mood than their peers on placebo.Still, the biotech pointed to other outcomes to make the case for the molecule.The phase 2 trial enrolled 69 people with major depressive disorder and elevated levels of anhedonia, a reduced ability to feel pleasure. Sixty-three patients completed the first part of the study, which assessed the effect of single 25 µg or 75 µg doses of the histamine H3 receptor inverse agonist ALTO-203 on a measure of alertness and mood. Patients in the multi-dose part of the trial took ALTO-203 once a day for 28 days.Alto reported significant improvements in alertness and mood five hours after a single dose of ALTO-203. The problem? Participants also improved on placebo. In a June 26 press release, Alto said the placebo response was higher than expected and there was no significant separation between ALTO-203 and the control.The measure of alertness and mood was the primary endpoint in the single-dose part of the study. While the trial missed the endpoint, Alto reported significant changes in an EEG marker, the theta/beta ratio, that it has flagged as a way to identify people who might respond to treatment. The biotech said patients with more abnormal theta/beta ratios at baseline had the biggest improvements in attention.Alto also linked ALTO-203 to increased wakefulness, as measured using wearables. In the multi-dose part of the trial, the biotech reported a mean placebo-adjusted improvement on the Montgomery-Åsberg Depression Rating Scale (MADRS) of 2 points at week 3 and 0.9 points at week 4. Alto saw the improvement over placebo on the low dose of the drug candidate. The high dose performed no better than placebo. The biotech expects to decide the next steps for ALTO-203 once it finishes the complete analysis of the dataset. At a Jefferies event earlier this month, Alto CEO Amit Etkin, M.D., Ph.D., discussed what the company was hoping to see in the results and how the insights would inform the next steps.“What we\'re hoping for is some clear signal that helps you guide how to develop it,” Etkin said. “Obviously, statistical significance is an important cut point there, but also is that signal similar to what we\'ve seen in healthy individuals? Does that signal help tell you what kind of clinical populations to develop it, be it in depression where it is now or anywhere else?”