Synthesis of the selective antimuscarinic agent 4-{[cyclohexylhydroxy(2-methoxyphenyl)silyl]-methyl}-1,1-dimethylpiperazinium methyl sulfate (o-methoxy-sila-hexocyclium methyl sulfate)

The synthesis of the potent and highly selective silicon-containing antimuscarinic agent o-methoxysila-hexocyclium methyl sulfate and its corresponding tertiary amine (isolated as the dihydrochloride) is described. The quarternary compound is an o-methoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The o-methoxy derivative, the pharmacological profile of which differs substantially from that of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.     

Translational medicine of the glutamate AMPA receptor

Psychiatric and neurological disorders severely hamper patient’s quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as “synapse diseases”. Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.     

计算受体和配体结合自由能的新方法

利用ABEEMσπ浮动电荷力场与连续介质模型相结合的方法,计算了受体和配体的结合自由能.将结合自由能分解为真空中的力场作用项、溶剂化能量以及熵效应.由于ABEEMσπ/MM方法充分考虑了外界环境发生变化引起的体系中各个位点之间的电荷极化,因而极大地提高了结合自由能的计算精度.利用该方法计算的2个复合物的结合自由能与实验值的偏差均小于0.5kJ/mol.     

Synthesis of the core structure of the lipoteichoic acid of Streptococcus pneumoniae

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2‐acetamino‐4‐amino‐2,4,6‐trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure Glcβ(1‐3)AATDgalβ(1‐3)Glcα(1‐O)DAG in a suitably protected form for further chain extension ( 1 b , 1 c ) and as unprotected glycolipid ( 1 a ) that was employed in biological studies. These studies revealed that 1 a as well as 1 lead to interleukin‐8 release, however not via TLR2 or TLR4 as receptor.     

Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits

The study investigated the effects of adenovirus-mediated gene transfection of basic fibroblast growth factor (bFGF), bFGF combined with interleukin-1 receptor antagonist protein (IL-Ra) and/or insulin-like growth factor-1 (IGF-1) both in human osteoarthritis (OA) chondrocytes and rabbits OA model. Human OA chondrocytes were delivered by adenovirus-mediated bFGF, IL-Ra and IGF-1 vectors, respectively. Chondrocyte proliferation, glycosaminoglycan (GAG) content, expression of type II collagen, ADAMTS-5, MMP-13, MMP-3 and TIMP-1 were determined. Rabbit OA model was induced by anterior cruciate ligament transaction (ACLT) in knees. Adenoviral vectors encoding human bFGF, IL-Ra and IGF-1 were injected intraarticularly into the knee joints after ACLT. The effects of adenovirus- mediated gene transfection on rabbit OA were evaluated. In vitro, the transfected genes were expressed in cell supernatant of human OA chondrocytes. AdbFGF group significantly promoted chondrocyte proliferation, and increased GAG and type II collagen synthesis than in the OA group. As two or three genes were transfected in different combinations, there was significant enhancement on the GAG content, type II collagen synthesis, and TIMP-1 levels, while ADAMTS-5, MMP-13, and MMP-3 levels were reduced. In vivo, the transfected genes were expressed in synovial fluid of rabbits. Intraarticular delivery of bFGF enhanced the expression of type II collagen in cartilage and decreased cartilage Mankin score compared with the OA control group (P = 0.047; P < 0.01, respectively). Multiple-gene transfection in different combinations showed better results than bFGF transfection alone. This study suggests that bFGF gene transfection is effective in treating experimental OA. Multiple gene transfection has better biologic effects on OA.     

TRPC3 cation channel plays an important role in proliferation and differentiation of skeletal muscle myoblasts

During membrane depolarization associated with skeletal excitation-contraction (EC) coupling, dihydropyridine receptor [DHPR, a L-type Ca²⁺ channel in the transverse (t)-tubule membrane] undergoes conformational changes that are transmitted to ryanodine receptor 1 [RyR1, an internal Ca²⁺-release channel in the sarcoplasmic reticulum (SR) membrane] causing Ca²⁺ release from the SR. Canonical-type transient receptor potential cation channel 3 (TRPC3), an extracellular Ca²⁺-entry channel in the t-tubule and plasma membrane, is required for full-gain of skeletal EC coupling. To examine additional role(s) for TRPC3 in skeletal muscle other than mediation of EC coupling, in the present study, we created a stable myoblast line with reduced TRPC3 expression and without α1_SDHPR (MDG/TRPC3 KD myoblast) by knock-down of TRPC3 in α1_SDHPR-null muscular dysgenic (MDG) myoblasts using retrovirus-delivered small interference RNAs in order to eliminate any DHPR-associated EC coupling-related events. Unlike wild-type or α1_SDHPR-null MDG myoblasts, MDG/TRPC3 KD myoblasts exhibited dramatic changes in cellular morphology (e.g., unusual expansion of both cell volume and the plasma membrane, and multi-nuclei) and failed to differentiate into myotubes possibly due to increased Ca²⁺ content in the SR. These results suggest that TRPC3 plays an important role in the maintenance of skeletal muscle myoblasts and myotubes.     

Neuroprotection signaling pathway of nerve growth factor and brain-derived neurotrophic factor against staurosporine induced apoptosis in hippocampal H19-7 cells

Neurotrophins protect neurons against excitotoxicity; however the signaling mechanisms for this protection remain to be fully elucidated. Here we report that activation of the phosphatidyl inositol 3 kinase (PI3K)/Akt pathway is critical for protection of hippocampal cells from staurosporine (STS) induced apoptosis, characterized by nuclear condensation and activation of the caspase cascade. Both nerve growth factor (NGF) and brain-derived growth factor (BDNF) prevent STS-induced apoptotic morphology and caspase-3 activity by upregulating phosphorylation of the tropomyosin receptor kinase (Trk) receptor. Inhibition of Trk receptor by K252a altered the neuroprotective effect of both NGF and BDNF whereas inhibition of the p75 neurotrophin receptor (p75NTR) had no effect. Impairment of the PI3K/Akt pathway or overexpression of dominant negative (DN)-Akt abolished the protective effect of both neurotrophins, while active Akt prevented cell death. Moreover, knockdown of Akt by si-RNA was able to block the survival effect of both NGF and BDNF. Thus, the survival action of NGF and BDNF against STS-induced neurotoxicity was mediated by the activation of PI3K/Akt signaling through the Trk receptor.     

1,3-双(1-苯基-1H-四唑-5-巯基)-乙酰苯腙钳形受体对卤素阴离子的识别机理

采用密度泛函B3LYP(Becke, three-parameter, Lee-Yang-Parr)和HF(Hatree-Fock)方法, 从理论上探讨了1,3-双(1-苯基-1H-四唑-5-巯基)-乙酰苯腙(DAPHZ)钳形受体对卤素阴离子的识别机理,结果发现DAPHZ受体以其钳形结构中的-N-H基团与卤素阴离子间形成双侧红移氢键进行识别. 经BSSE校正后DAPHZ•••F-, DAPHZ•••Cl-和DAPHZ•••Br-体系的分子识别相互作用能ΔECP分别为-327.5,-163.5和-148.3 kJmol-1, 说明钳形DAPHZ受体对F-具有最好的识别能力. 此外, 采用自然键轨道(NBO)计算, 相关H原子化学位移计算及分子中原子(AIM)等理论分析了识别体系中红移氢键的电子结构和性质, 结果表明APHZ受体对卤素阴离子的识别能力的相对顺序为DAPHZ•••F- >> DAPHZ•••Cl- ≈ DAPHZ•••Br-.     

Discovery of a Novel 5-HT_(2A) Inhibitor by Pharmacophore-based Virtual Screening

The serotonin 2A(5-HT2A) receptor has been implicated in several neurological conditions and potent 5-HT2A antagonists have therapeutic effects in the treatment of schizo phrenia and depression.In this study,a potent novel 5-HT2A inhibitor 05245768 with a Ki value of (593.89±34.10) nmol/L was discovered by integrating a set of computational approaches and experiments(protein structure prediction,pharmacophore-based virtual screening,automated molecular docking and pharmacological bioassay).The 5-HT2A recept...     

The Syntheses of Triazinone and Pyrimidinone Biphenyltetrazoles as Angiotensin II Receptor Antagonists

A series of biphenylyltetrazole substituted triazinones and structure-related pyrimidinones are systhesized, and their binding affinities for angiotensin II receptor are reported.