组胺H3受体拮抗剂的研究进展

组胺H3受体不仅参与调节脑内组胺的释放、合成与代谢,还能调节其它多种神经递质的释放与代谢。它与中枢神经系统的诸多神经行为功能有密切关系。因此组胺H3受体拮抗剂的新药开发有望用于临床治疗精神行为紊乱型疾病如老年性痴呆、帕金森氏综合征等。本文简单介绍了组胺H3受体的组织分布及功能,着重综述了各种H3受体拮抗剂的研究概况。     

组胺H_3受体激动剂与拮抗剂

组胺Ｈ_３受体激动剂与拮抗剂罗晓星，谭月华（第四军医大学药理教研室，西安７１００３２）组胺受体药理学研究方面曾经有过两次重大突破：１９３７年Ｂｏｖｅｔ首先发现了经典的＂抗组胺药＂（亦即现在的Ｈ１受体拮抗剂）［１］，１９７２年Ｂｌａｃｋ创制成功Ｈ２受体?..     

组胺H3受体研究新进展

组胺H3受体广泛分布于组胺能神经末梢的突触前膜,不仅参与调节脑内组胺的释放、合成与代谢,而且参与调节脑内5-羟色胺(5-HT)、去甲肾上腺素(NE)、乙酰胆碱(Ach)、神经肽等多种神经递质的释放与代谢。它可以调节中枢神经系统的诸多神经行为功能,诸如学习记忆、癫痫、自发运动、觉醒与睡眠以及饮水饮食行为等。另外还参与调节胃肠道、呼吸道、血管、心脏等外周器官的诸多功能活动。组胺H3受体拮抗剂thioperamide、clobenpropit等极可能作为一类新的药物,用于临床治疗精神行为紊乱性疾病如老年性痴呆、癫痫、偏头痛以及帕金森氏综合征等。     

第二代组胺H1受体拮抗剂

目的：对第二代H1受体拮抗剂的作用特点、疗效及不良反应等进行综合评述。方法：以国外发表的文献为依据,对第二代H1受体拮抗剂的临床 应用和注意问题进行介绍。结果：第二代H1受体拮抗剂能减少或消除第一代H1受体拮抗剂所产生的镇静和抗胆碱能不良反应,对H1受体具有较强的选择性。结论：临床使用无明显的精神运动性损害,是治疗鼻炎、荨麻疹和皮炎的有效药物。     

非咪唑类组胺H3受体拮抗药的研究进展

（1. ［摘要］组胺H3受体是新近发现的一种组胺受体的新亚型。近年来,以组胺H3受体作为靶点,设计和开发出的一些候选的H3受体拮抗药在治疗一些中枢神经系统疾病（如阿尔茨海默病 、帕金森病）等方面有一定的应用前景。目前H3受体拮抗药研究的重点已从经典的咪唑类H3受体拮抗药逐步向非咪唑类的H3受体拮抗药转变。     

治疗发作性睡病新药——组胺H_3受体拮抗剂和反向激动剂哌托生特

哌托生特为一种口服有效的组胺H3受体拮抗剂和反向激动剂,由法国Bioproject公司开发,于2016年3月31日获欧盟批准用于治疗成人伴或不伴猝倒的发作性睡病。临床试验证实与安慰剂相比哌托生特能够明显降低发作性睡病患者白日过度睡眠,也能够明显降低猝倒发生率。哌托生特最常见的不良反应为失眠、头痛、恶心、焦虑、兴奋、头晕及抑郁等。     

第二代组胺H_1受体拮抗剂

目的:对第二代H1受体拮抗剂的作用特点、疗效及不良反应等进行综合评述。方法:以国外发表的文献为依据,对第二代H1受体拮抗剂的临床应用和注意问题进行介绍。结果:第二代H1受体拮抗剂能减少或消除第一代H1受体拮抗剂所产生的镇静和抗胆碱能不良反应,对H1受体具有较强的选择性。结论:临床使用无明显的精神运动性损害,是治疗鼻炎、荨麻疹和皮炎的有效药物。     

组胺H1受体拮抗剂的研究与开发

简介组胺H1受体活性及结合位点，综述二苯并[a，d[7]轮烯-5-胺类、1，2，4-三唑并[4，3-a]喹唑啉-5（4H）-酮类、咪唑[1，2-a]吡咯[3，2-d]氮杂[艹卓]类、苯并[5，6]环庚基[1，2．b]吡啶类、（ω、ω-二苯烷基）-1H-咪唑类、4-吲哚基哌啶取代苯甲酸类以及N-羟基氨基甲酸酯类H1受体拮抗剂的作用机制和构效关系。作为抗过敏性疾病的主要药物之一，H1受体拮抗剂能竞争性地与H1受体结合，阻断组胺与H1受体作用，从而抑制组胺的生物学效应。     

The histamine H3 receptor: from discovery to clinical trials with pitolisant

The third histamine receptor was discovered in 1983 by a traditional pharmacological approach, consisting of assessing the inhibitory effect of histamine on its own release from depolarized rat brain slices. The same in vitro test was used to design, in 1987, the first highly selective and potent H3-autoreceptor ligands, the antagonist thioperamide and the agonist (R)alphamethylhistamine which enhances and inhibits, respectively, the activity of histaminergic neurons in brain. The use of these research tools was instrumental in establishing the main functions of cerebral histaminergic neurons, namely their role in maintenance of wakefulness, attention, learning and other cognitive processes. In 1990, the cloning of the gene of the H3-receptor, a member of the superfamily of heptahelical receptors coupled to G proteins, paved the way to the demonstration of the high constitutive activity of the receptor, including its native form, and its participation in the tonic control of histamine release; it also facilitated the development of H3-receptor inverse agonist programs in many drug companies. Pitolisant (BF2.649, 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride) is the first inverse agonist to be introduced in the clinics. Its wake-promotion activity was evidenced in excessive diurnal sleepiness of patients with narcolepsy, Parkinson's disease or Obstructive Sleep Apnea/Hypopnea, in which this activity is characterized by a mean decrease of the Epworth Sleepiness Scale by about five units. The procognitive activity of this novel class of drugs may also find therapeutic applications in dementias, schizophrenia or attention deficit hyperactivity disorder.     

新型组胺受体:组胺H_4受体

组胺H4受体是近年发现的组胺新受体 ,它具有独特的药理学性质和特殊的组织分布特征 ,与组胺H3 受体有较高的同源性。该文对组胺H4受体的基因结构、组织分布、同源性分析、信号转导途径及与组胺配体亲和力等方面进行综述 ,并对其未来研究前景进行了展望。     

组胺H_3受体对心血管系统的调控作用

综述了组胺H3受体的细胞内信号转导途径 ,在心血管系统对一些神经递质的调控作用及组胺H3受体激动剂对于心血管系统疾病潜在的应用前景     

SAR exploration of the non-imidazole histamine H3 receptor ligand ZEL-H16 reveals potent inverse agonism

Histamine H₃ receptor (H₃R) agonists without an imidazole moiety remain very scarce. Of these, ZEL-H16 ( 1 ) has been reported previously as a high-affinity non-imidazole H₃R (partial) agonist. Our structure-activity relationship analysis using derivatives of 1 identified both basic moieties as key interaction motifs and the distance of these from the central core as a determinant for H₃R affinity. However, in spite of the reported H₃R (partial) agonism, in our hands, 1 acts as an inverse agonist for Gα_i signaling in a CRE-luciferase reporter gene assay and using an H₃R conformational sensor. Inverse agonism was also observed for all of the synthesized derivatives of 1 . Docking studies and molecular dynamics simulations suggest ionic interactions/hydrogen bonds to H₃R residues D114^3.32 and E206^5.46 as essential interaction points.     

The cloning of the human histamine H3 receptor

The polynucleotide sequence of the gene encoding the human histamine H₃ receptor was identified by mining expressed sequence tag (EST) libraries. The gene has been cloned and the receptor expressed in a variety of cell lines. Like other amine transmitter receptors, the cloned histamine H₃ receptor appears to be a G protein-coupled receptor (GPCR) and has been characterised in vitro using existing pharmacological tools. This invention may have many consequences for the histamine H₃ area. It has already resulted in the cloning of guinea-pig and rat histamine H₃ receptors and the use of the human receptor in high-throughput screens for the identification of potential drug candidates.     

Effects of the histamine H3 receptor antagonist ABT-239 on cognition and nicotine-induced memory enhancement in mice

BackgroundThe strong correlation between central histaminergic and cholinergic pathways on cognitive processes has been reported extensively. However, the role of histamine H₃ receptor mechanisms interacting with nicotinic mechanisms has not previously been extensively investigated.MethodsThe current study was conducted to determine the interactions of nicotinic and histamine H₃ receptor systems with regard to learning and memory function using a modified elevated plus-maze test in mice. In this test, the latency for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. We tested whether ABT-239 (4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl), an H₃ receptor antagonist/inverse agonist, had influence on two different stages of memory, i.e., memory acquisition and consolidation (administered prior to or immediately after the first trial, respectively) and whether ABT-239 influenced nicotine-induced memory enhancement.ResultsOur results revealed that the acute administration of nicotine (0.035 and 0.175 mg/kg), but not of ABT-239 (0.1–3 mg/kg) reduced transfer latency in the acquisition and consolidation phases. In combination studies, concomitant administration of either ABT-239 (1 and 3 mg/kg) and nicotine (0.035 mg/kg), or ABT-239 (0.1 mg/kg) and nicotine (0.0175 mg/kg) further increased nicotine-induced improvement in both memory acquisition and consolidation.ConclusionThe present data confirm an important role for H₃ receptors in regulating nicotine-induced mnemonic effects since inhibition of H₃ receptors augmented nicotine-induced memory enhancement in mice.     

Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas

The neurotransmitter histamine exerts its action through four distinct histamine receptors. The histamine H₁ and H₂ receptor are well established drug targets, whereas the histamine H₄ receptor is undergoing rigorous characterisation at present. The histamine H₃ receptor (H₃R) is a G_i/o-protein coupled receptor and is mostly expressed in the CNS. A remarkably large and different array of therapeutic areas, in which ligands for the H₃R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H₃R ligands. At present, several ligands for the H₃R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H₃R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H₃R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H₃R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H₃R drugs will reach the market soon.     

奥洛他定的合成

目的：合成新型H1受体阻滞剂奥洛他定。方法：以对羟基苯乙酸和苯酞为原料，经取代、环合、维蒂希反应等9步反应合成目标产物。结果与结论：合成了目标产物，其结构经MS和^1H—NMR确定。     

Pharmacokinetics and tissue distribution of the new non-imidazole histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy) propyl]piperidine in rats

Abstract

1.?The aim of this study was to evaluate pharmacokinetics and tissue distribution of novel histamine H3 receptor antagonist 1-[3-(4-tert-butylphenoxy)propyl]piperidine (compound DL76).

2.?Following intravenous administration of DL76 at the dose of 3?mg/kg, pharmacokinetic parameters were calculated using non-compartmental analysis. The systemic serum clearance was 10.08?L/h/kg and the estimated blood clearance was 5.64?L/h/kg. The volume of distribution at steady state was 16.1?L/kg which was greater than total body water, terminal half-life and MRT equalled 1.41?h and 1.6?h, respectively. The two-compartment pharmacokinetic model with enterohepatic circulation was also successfully fitted to the experimental data.

3.?After systemic administration, DL76 was rapidly distributed into all organs studied (liver, kidney, brain, and lung). The highest AUC of DL76 was observed in lungs followed by brain, where the exposure to the investigated compound expressed as AUC was almost 30 times higher than in serum.

4.?Bioavailability, calculated based on the area-under-the-concentration–time curve extrapolated to infinity after intravenous and intragastric administration of the dose 3?mg/kg, equalled 60.9%.     

Effects of the histamine (H)3 receptor antagonist ABT-239 on acute and repeated nicotine locomotor responses in rats

The addictive potential of nicotine is linked to psychomotor and cognition-enhancing effects. Histamine (H)(3) receptor antagonism has similarly received attention for a role in cognition, however, the role of H(3) receptors are far less studied for affects on nicotine-induced locomotor responses. In the present study we tested whether the H(3) receptor antagonist 4-(2-{2-[(2R)-2 methylpyrrolidinyl] ethyl}-benzofuran-5-yl) benzonitrile (ABT-239) influenced the psychomotor responses to acute and repeated nicotine, including sensitization and conditioned locomotion. ABT-239 (0.3-3 mg/kg) did not alter basal, nicotine-evoked (0.4 mg/kg) locomotor responses, the expression of sensitization, or cue-conditioned locomotion. However, in combination studies rats pretreated with a separate dose of ABT-239 (1 mg/kg) prior to nicotine (0.4 mg/kg) for 5 days and then challenged with nicotine (0.4 mg/kg) after a 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in nicotine-pretreated and challenged rats. Our findings implicate a limited role for H(3) receptors in locomotor responses to nicotine.