Progress in the development of histamine H3 receptor antagonists/inverse agonists: a patent review (2013-2017)

Introduction: Since years, ligands blocking histamine H₃ receptor (H₃R) activity (antagonists/inverse agonists) are interesting targets in the search for new cures for CNS disorders. Intensive works done by academic and pharmaceutical company researchers have led to many potent and selective H₃R antagonists/inverse agonists. Some of them have reached to clinical trials.

Areas covered: Patent applications from January 2013 to September 2017 and the most important topics connected with H₃R field are analysed. Espacenet, Patentscope, Pubmed, GoogleScholar or Cochrane Library online databases were principially used to collect all the materials.

Expert opinion: The research interest in histamine H₃R field is still high although the number of patent applications has decreased during the past 4 years (around 20 publications). Complexity of histamine H₃R biology e.g. many isoforms, constitutive activity, heteromerization with other receptors (dopamine D₂, D₁, adenosine A_2A) and pharmacology make not easy realization and evaluation of therapeutic potential of anti-H₃R ligands. First results from clinical trials have verified potential utility of histamine H₃R antagonist/inverse agonists in some diseases. However, more studies are necessary for better understanding of an involvement of the histaminergic system in CNS-related disorders and helping more ligands approach to clinical trials and the market.

Lists of abbreviations: hAChEI – human acetylcholinesterase inhibitor; hBuChEI – human butyrylcholinesterase inhibitor; hMAO – human monoamine oxidase; MAO – monoamine oxidase     

A novel Fc gamma receptor ligand augments humoral responses by targeting antigen to Fc gamma receptors

Generating efficient antibody (Ab) responses against weak antigens remains challenging. Ab responses require antigen (Ag) uptake by antigen-presenting cells (APC), followed by presentation of processed Ag to T cells. Limited uptake of antigenic peptides by APC constrains Ab responses. Here we improve vaccine efficacy by targeting Ag to Fcgamma receptors (FcgammaR) using R4, a recombinant FcgammaR ligand. R4 has four repeats per chain of the hinge region and CH2 domain (HCH2) of human IgG1. HCH2 encompasses the FcgammaR binding site. The repeats are linked to the human IgG1 framework. To test R4 in augmenting Ag uptake, we expressed human serum albumin domain 1 (HSA1) at the N terminus of R4 to produce HSA1R4. HSA1R4 (50 microg) administered to mice in Ribi adjuvant induces up to 1100-fold higher HSA1-specific IgG titers than HSA1 (p<0.001). HSA1R4 (250 ng) induces up to 130 times more anti-HSA1 Ab than HSA1Fc, a protein with HSA1 linked to the IgG1 framework (p<0.001). HSA-reactive T cells proliferate more briskly to HSA1R4 than to HSA1Fc (p<0.008). Immunization with HSA1R4 yields greater T cell reactivity to HSA1 ex vivo than immunization with HSA1Fc (p<0.004). Linking antigenic peptides to linear HCH2 polymers may facilitate vaccine development.     

偏向性配体——阿片类镇痛药设计新思路

吗啡等阿片类药物作为镇痛药应用已有数百年历史,但其致呼吸抑制、耐受和成瘾等副作用限制了该类药物的使用,因此人们一直致力于寻找副作用更低的新型镇痛药。近年研究发现,μ阿片受体下游除了经典的G 蛋白依赖型通路外,还独立存在由β-arrestin 介导的信号通路,吗啡激活μ阿片受体产生的镇痛、镇静效应主要通过G 蛋白依赖型通路介导,而胃肠功能紊乱、呼吸抑制、耐受等副反应则由β-arrestin 依赖型通路介导。如果能发现只激活G 蛋白依赖型通路而不激活β-arrestin 依赖型通路的偏向性配体,就可能得到镇痛效应强而副作用低的化合物,这为设计新型强效、低副作用的阿片类镇痛药提供了新思路。该文将对μ阿片受体下游β-arrestin 依赖型信号通路及偏向性配体的发现、发展和应用进行综述。     

Gut microbiota regulates NKG2D ligand expression on intestinal epithelial cells

Intestinal epithelial cells (IECs) are one of a few cell types in the body with constitutive surface expression of natural killer group 2 member D (NKG2D) ligands, although the magnitude of ligand expression by IECs varies. Here, we investigated whether the gut microbiota regulates the NKG2D ligand expression on small IECs. Germ‐free and ampicillin‐treated mice were shown to have a significant increase in NKG2D ligand expression. Interestingly, vancomycin treatment, which propagated the bacterium Akkermansia muciniphila and reduced the level of IFN‐γ and IL‐15 in the intestine, decreased the NKG2D ligand expression on IECs. In addition, a similar increase in A. muciniphila and a decreased NKG2D ligand expression was seen after feeding with dietary xylooligosaccharides. A pronounced increase in NKG2D ligand expression was furthermore observed in IL‐10‐deficient mice. In summary, our results suggest that the constitutive levels of NKG2D ligand expression on IECs are regulated by microbial signaling in the gut and further disfavor the intuitive notion that IEC NKG2D ligand expression is caused by low‐grade immune reaction against commensal bacteria. It is more likely that constitutively high IEC NKG2D ligand expression is kept in check by an intestinal regulatory immune milieu induced by members of the gut microbiota, for example A. muciniphila.     

Development of M1 mAChR Allosteric and Bitopic Ligands: Prospective Therapeutics for the Treatment of Cognitive Deficits

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Design,Synthesis and Biological Evaluation of Two Opioid Agonist and Cav2.2 Blocker Multitarget Ligands

N‐type voltage‐dependent Ca²⁺ channels (Ca_V2.2) are located at nerve endings in the central and peripheral nervous systems and are strongly associated with the pathological processes of cerebral ischaemia and neuropathic pain. Ca_V2.2 blockers such as the ω‐conotoxin MVIIA (Prialt) are analgesic and have opioid‐sparing effects. With the aim to develop new multitarget analgesic compounds, we designed the first ω‐conotoxin/opioid peptidomimetics based on the enkephalin‐like sequence Tyr‐D‐Ala‐Gly‐Phe (for the opioid portion) and two fragments derived from the loop‐2 pharmacophore of ω‐conotoxin MVIIA. Antinociceptive activity evaluated in vitro and in vivo revealed differential affinity for Ca_V2.2 and opioid receptors and no significant synergistic activity.     

结核丸联合常规抗结核方案治疗老年肺结核合并颈部淋巴结核的临床研究

目的：评价结核丸联合常规抗结核方案治疗老年肺结核合并颈部淋巴结核的临床疗效。方法2012年1月－2014年1月共纳入河北省胸科医院胸三科103例合并颈部淋巴结核老年肺结核患者,并按随机数字表法将患者随机分为常规抗结核方案组（对照组）51例和结核丸联合常规抗结核方案组（治疗组）52例。对照组采用常规抗结核方案（2HRZE/4HR）治疗;治疗组在对照组治疗基础上加服结核丸治疗。2组均先采用标准化抗结核药物治疗4周后,行颈淋巴结结核病灶摘（清）除术,脓肿性结节行切开引流术。2组均治疗6个月后检测痰涂片,流式细胞术检测外周血CD8细胞上自然杀伤（NK）T细胞表面受体NKG2D和NKG2A表达及血清白细胞介素（IL）-6、IL-10、肿瘤坏死因子-α（TNF-α）水平变化,并进行临床疗效评价。结果治疗组病灶吸收率为78.85%（41/52）,显著高于对照组的58.82%（30/51）（χ2＝4.439,P＜0.05）;空洞闭合率为62.86%（22/35）,也显著高于对照组的35.48%（11/31）（χ2＝3.893, P＜0.05）。治疗组2、4、6个月末累计痰菌阴转率显著高于对照组（χ2值分别为5.343、5.067和4.118, P均＜0.05）。治疗组治疗后表达 NKG2A的CD8细胞显著低于同组治疗前和对照组治疗后（t值分别为9.510、9.832,P均＜0.01）;表达NKG2D的CD8细胞显著高于同组治疗前和对照组治疗后（t值分别为10.622、10.433,P均＜0.01）。2组血清IL-6、TNF-α水平均较同组治疗前下降（治疗组t值分别为17.344、21.142,对照组t值分别为10.984、12.203,P均＜0.01）,且治疗组治疗后低于对照组治疗后（t值分别为7.832、5.478,P均＜0.01）。2组血清IL-10水平均明显高于同组治疗前（t 治疗组＝12.454、t 对照组＝7.934, P均＜0.01）,且治疗组治疗后高于对照组治疗后（t＝4.720,P＜0.01）。治疗组淋巴结核有效率（46/52,88.5%）高于对照组（33/51,64.7%）（χ2＝6.855,P＜0.01）。结论结核丸联合常规抗结核方案治疗可提高患者的免疫功能及痰菌阴转率,促进病灶吸收。     

Critical roles of co‐activation receptor DNAX accessory molecule‐1 in natural killer cell immunity

Natural killer (NK) cells, which can exert early and powerful anti‐tumour and anti‐viral responses, are important components of the innate immune system. DNAX accessory molecule‐1 (DNAM‐1) is an activating receptor molecule expressed on the surface of NK cells. Recent findings suggest that DNAM‐1 is a critical regulator of NK cell biology. DNAM‐1 is involved in NK cell education and differentiation, and also plays a pivotal role in the development of cancer, viral infections and immune‐related diseases. However, tumours and viruses have developed multiple mechanisms to evade the immune system. They are able to impair DNAM‐1 activity by targeting the DNAM‐1 receptor–ligand system. We have reviewed the roles of DNAM‐1, and its biological functions, with respect to NK cell biology and DNAM‐1 chimeric antigen receptor‐based immunotherapy.