Double-blind, Placebo Controlled, Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BP1.5375 After Single Oral Administrations Ranging From 0.5 mg to 100 mg in Healthy Male Subjects (Part 1) Followed by the Assessment of the Effect of 3 Single Different BP1.5375 Oral Doses on Polysomnography in Comparison to 50 mg Diphenhydramine and Placebo in Healthy Male Subjects (Part 2).

Phase I Single Ascending Dose (Part 1), phase IIa Proof Of Concept (Part 2)

开始日期2014-10-01

申办/合作机构

Bioprojet Pharma SARL

100 项与 Immethridine Dihydrobromide 相关的临床结果

登录后查看更多信息

100 项与 Immethridine Dihydrobromide 相关的转化医学

登录后查看更多信息

100 项与 Immethridine Dihydrobromide 相关的专利（医药）

登录后查看更多信息

项与 Immethridine Dihydrobromide 相关的文献（医药）

2022-01-01·Pharmacology, biochemistry, and behavior

Histamine H3 receptor antagonism modulates autism-like hyperactivity but not repetitive behaviors in BTBR T+Itpr3tf/J inbred mice

Article

作者: Hutten, Lianda ; Kas, Martien J H ; Molenhuis, Remco T

BACKGROUND:

Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by behavioral deficits in social communication and interactions, mental inflexibility and repetitive behaviors. Converging evidence from observational and preclinical studies suggest that excessive repetitive behaviors in people with ASD may be due to elevated histaminergic H3 receptor signaling in the striatum. We hypothesized that systemic administration of pharmacological histamine H3 receptor antagonists would attenuate the expression of repetitive behaviors in the BTBR T+Itpr3tf/J (BTBR) mouse inbred strain, an established mouse model presenting autism-like repetitive behaviors and novelty-induced hyperactivity. We further aimed to investigate whether agonism of the histamine H3 receptor would be sufficient to induce repetitive behaviors in the C57BL/6J control mouse strain.

METHODS:

Different doses of H3 receptor agonists (i.e., (R)-α-methylhistamine and immethridine) and H3 receptor antagonists/inverse agonists (i.e., ciproxifan and pitolisant) were administered via intraperitoneal (i.p.) injection in male mice to characterize the acute effects of these compounds on ASD-related behavioral readouts.

RESULTS:

The highly selective H3 receptor agonist immethridine significantly increased the time spent in stereotypic patterns in C57BL/6J mice, but this effect appeared to be driven by general sedative properties of the compound. High doses of pitolisant significantly decreased locomotor hyperactivity in novel environments in BTBR mice, without significant effects on repetitive behaviors.

CONCLUSIONS:

Based on our findings, we conclude that acute H3 receptor manipulation mainly affected general motor activity levels in novel environments. Small changes in stereotyped behaviors were observed but appeared to be driven by altered general activity levels.

2020-02-11·Proceedings of the National Academy of Sciences of the United States of America1区 · 综合性期刊

Histamine receptor agonist alleviates severe cardiorenal damages by eliciting anti-inflammatory programming

1区 · 综合性期刊

Article

作者: Usui, Joichi ; Kawasaki, Shohei ; Ishimaru, Tomohiro ; Muromachi, Naoto ; Lu, Weizhe ; Fukamizu, Akiyoshi ; Yamagata, Kunihiro ; Mizukami, Hayase ; Noguchi, Kazuyuki ; Ohtsu, Hiroshi ; Kako, Koichiro ; Ishida, Junji ; Kaneko, Shuzo ; Kim, Jun-Dal

Heart failure and chronic kidney disease are major causes of morbidity and mortality internationally. Although these dysfunctions are common and frequently coexist, the factors involved in their relationship in cardiorenal regulation are still largely unknown, mainly due to a lack of detailed molecular targets. Here, we found the increased plasma histamine in a preclinical mouse model of severe cardiac dysfunction, that had been cotreated with angiotensin II (Ang II), nephrectomy, and salt (ANS). The ANS mice exhibited impaired renal function accompanied with heart failure, and histamine depletion, by the genetic inactivation of histidine decarboxylase in mice, exacerbated the ANS-induced cardiac and renal abnormalities, including the reduction of left ventricular fractional shortening and renal glomerular and tubular injuries. Interestingly, while the pharmacological inhibition of the histamine receptor H3 facilitated heart failure and kidney injury in ANS mice, administration of the H3 agonist immethridine (Imm) was protective against cardiorenal damages. Transcriptome analysis of the kidney and biochemical examinations using blood samples illustrated that the increased inflammation in ANS mice was alleviated by Imm. Our results extend the pharmacological use of H3 agonists beyond the initial purposes of its drug development for neurogenerative diseases and have implications for therapeutic potential of H3 agonists that invoke the anti-inflammatory gene expression programming against cardiorenal damages.

2017-09-26·Oncotarget

Immethridine, histamine H3-receptor (H3R) agonist, alleviated experimental autoimmune encephalomyelitis via inhibiting the function of dendritic cells

Article

作者: Hu, Xuefei ; Shi, Yaru ; He, Cong ; Li, Zhenlong ; Zhang, Jiang ; Su, Qiong ; Cui, Shufang ; Ma, Hongdou ; Chen, Ran ; Jiang, Wenzheng ; Ren, Hua ; Qian, Min

Multiple sclerosis (MS) is an inflammatory disease that is characterized by immune-mediated demyelination and degeneration of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is the preferential experimental rodent model for MS. Previous study demonstrated histamine H3 receptor (H3R) was an important factor in pathophysiology of EAE and immethridine was the most selective agonist of H3R. However, whether immethridine has therapeutic effect on EAE and its mechanism remained to be defined. Here we constructed EAE mouse model by immunization of MOG_35-55 peptides with complete Freund's adjuvant, immethridine was used to treat EAE and its therapeutic effect was evaluated. The results showed that the treatment of immethridine could alleviate EAE. The percentage of Th1 and Th17 in the spleen from the treated EAE mice decreased and the surface molecules such as CD40, CD86 or MHCII on dendritic cells (DCs) were also down-regulated. To understand the effect of immethridine on DCs, bone marrow-derived DCs were prepared and the immunological functions were analyzed. The data demonstrated that immethridine could change the expression profiles of cytokines in DCs and inhibit the expression of the co-stimulatory molecules such as CD40 and CD86. Furthermore, immethridine also inhibited the antigen-presenting function of DCs and T cell differentiation induced by DCs. Signaling pathway analysis demonstrated that the phosphorylation of NF-κB p65 but not ERK1/2 in DCs was inhibited after the treatment of immethridine. These data strongly suggested that immethridine could inhibit the function of DCs and indicated the therapeutic potential on EAE.

项与 Immethridine Dihydrobromide 相关的新闻（医药）

2024-10-04

·生物探索

Nat Commun｜龚为民/孙金鹏团队合作揭示整个组胺受体家族的配体识别及激活的分子机制

引言组胺是一种广泛分布的生物胺，是中枢神经系统中的神经递质，也是免疫系统、肠道和皮肤中的重要信号分子。组胺在人体中广泛存在，由肥大细胞、肠嗜铬样细胞和神经元等细胞分泌，参与一系列重要生理过程的调节，包括过敏反应、胃酸分泌、觉醒和炎症反应等。许多组胺功能由 G 蛋白偶联组胺受体介导，其中包括四个成员，H1R、H2R、H3R 和 H4R。事实上，长期以来人们一直认为组胺释放引起的炎症反应是由组胺 H1 受体介导的，而 H1 受体拮抗剂（通常称为抗组胺药）多年来一直用于治疗过敏。常用的组胺H1受体拮抗剂，如苯海拉明、异丙嗪、氯苯那敏等，是目前应用最广泛的非特异性抗过敏药物。此外，H2受体拮抗剂，如西咪替丁、尼扎替丁、雷尼替丁等，被广泛用于抑制胃酸过度分泌，治疗十二指肠溃疡、胃溃疡、胃食管反流、胃灼热等消化性溃疡病。此外，H3R拮抗剂匹特里赞特（Waxx®）已获批用于治疗发作性睡病和阻塞性睡眠呼吸暂停（Ozawade®）。组胺受体激动剂的药物开发进展则相对滞后。H1R的激动剂在理论上有可能调节神经系统的认知、觉醒等功能，但在外周组织中有促炎作用，目前定位的困难使其难以作为相关疾病的药物进行开发。H2R的激动剂则被研究发现有可能用于急性髓性白血病的治疗。H3R集中分布于神经系统，其激动剂不会在外周组织中引起副作用，因此很有潜力作为相关神经系统疾病如强迫性障碍的药物。H4R的激动剂也具有促炎作用，但用于疾病治疗的可能性有待于进一步研究。 2024年9月27日，中国科学技术大学龚为民课题组与山东大学孙金鹏课题组合作在Nature Communications杂志在线发表了题为Structural basis of ligand recognition and activation of the histamine receptor family的研究论文，系统报道了在内源性组胺或其他合成配体存在下，四种组胺家族受体亚型与四种不同的下游 G 蛋白复合的九种低温电子显微镜 (cryo-EM) 结构。该研究为理解所有四种组胺受体的配体识别和 G 蛋白偶联提供了一个结构框架，这可能有助于合理设计针对这些受体的配体。图组胺受体与相应 G 蛋白复合体的整体结构（Credit: Nature Communications）研究人员发现在组胺结合的H1R-Gq、H2R-Gs/q、H3R-Gi和H4R-Gi复合物中，酸性残基D3.32在组胺识别中起着关键作用，正如许多G蛋白偶联受体（GPCRs）在识别生物胺类分子时一样。同时，所有组胺受体的两个疏水残基Y/V3.33和Y6.51与组胺相互作用。D3.32-Y/V3.33-Y6.51基序在所有组胺受体中共享，表明该基序在组胺识别中起着关键作用。有趣的是，组胺在H3R和H4R的配体口袋中的结合方向与在H1R和H2R中的观察结果相反，这源于咪唑环旋转了约180°。进一步的结构和序列比较以及突变研究发现，H1R和H2R的TM6中保守的F6.52X2F6.55和H3R与H4R的TM7中的F7.39X3W7.43是决定这些不同结合方向的关键因素。结构比较显示，H1R和H2R的配体结合口袋与H3R和H4R的明显不同。H1R和H2R中存在两个特定口袋（正构口袋和次级结合口袋），而H3R和H4R中则存在三个特定口袋（正构口袋、次级结合口袋以及跨膜亚口袋）。这些口袋中的残基差异可以用于设计特异性靶向组胺受体成员的配体。此外，结构和药理学分析表明，immethridine （H3R选择性配体）刚性吡啶环与 H3R 中 L4017.42 的特异性相互作用是其对 H3R 而非 H4R 选择性的关键决定因素。H3R 中的 L4017.42 与 H4R 中的 Q3477.42 之间的序列差异也可以用于设计专门靶向 H3R 或 H4R 的配体。此外，研究人员发现在H2R胞质侧的ICL3是Gs/Gq耦合差异的决定因素。一个有趣的后续问题是，不同的组胺受体成员如何选择性地与Gs或Gi/Go蛋白耦合。研究人员通过更深入的结构和药理学分析发现，H2R的TM5与Gs更紧密的结合方式，以及H3R和H4R的R34.54-F/V6.25-R6.29基序与Gi/Go的独特相互作用，是不同组胺受体成员之间Gs和Gi/o选择性的基础。此项研究不仅可以进一步加深我们对整个组胺受体家族配体识别、激活及G蛋白耦合机制的理解，还可能有助于设计选择性靶向组胺受体家族成员的配体。参考文献 https://www-nature-com.libproxy1.nus.edu.sg/articles/s41467-024-52585-y 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

100 项与 Immethridine Dihydrobromide 相关的药物交易

登录后查看更多信息