Carbazole and tetrahydro-carboline derivatives as dopamine D_(3) receptor antagonists with the multiple antipsychotic-like properties

Dopamine D_(3) receptor(D_(3)R)is implicated in multiple psychotic symptoms.Increasing the D_(3)R selectivity over dopamine D_2 receptor(D_2R)would facilitate the antipsychotic treatments.Herein,novel carbazole and tetrahydro-carboline derivatives were reported as D_(3)R selective ligands.Through a structure-based virtual screen,ZLG-25(D_(3)R K_i=685 nmol/L;D_2R K_i>10,000 nmol/L)was identified as a novel D_(3)R selective bitopic ligand with a carbazole scaffold.Scaffolds hopping led to the discovery of novel D_(3)R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core.Further functional studies showed that most derivatives acted as h D_(3)R-selective antagonists.Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity.Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction.Furthermore,36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests,and alleviated the MK-801-induced disruption of novel object recognition in mice.Additionally,preliminary studies confirmed the favorable PK/PD profiles,no weight gain and limited serum prolactin levels in mice.These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Discovery of C19-9 as a novel non-RGD inhibitor of αvβ3 to overcome enzalutamide resistance in castration-resistant prostate cancer

Dear Editor,The integrinαvβ3 receptor is a promising target for anticancer therapy.1,2 However,there are no effective marketed treatments targetingαvβ3.One possible limitation of Arginine-Glycine-Aspartic(RGD)-mimeticαvβ3 antagonists has been shown to cause partial agonism,which could induce major conformational changes that trigger paradoxical cell adhesion and angiogenesis.

Multi-coefficient eigenmode operation—breaking through 10°/h open-loop bias instability in wideband aluminum nitride piezoelectric BAW gyroscopes

In this paper,a modification to the eigenmode operation of resonant gyroscopes is introduced.The multi-coefficient eigenmode operation can improve cross-mode isolation due to electrode misalignments and imperfections,which is one of the causes of residual quadrature errors in conventional eigenmode operations.A 1400µm annulus aluminum nitride(AlN)on a silicon bulk acoustic wave(BAW)resonator with gyroscopic in-plane bending modes at 2.98 MHz achieves a nearly 60 dB cross-mode isolation when operated as a gyroscope using a multi-coefficient eigenmode architecture.The as-born frequency mismatches in multiple devices are compensated by physical laser trimming.The demonstrated AlN piezoelectric BAW gyroscope shows a large open-loop bandwidth of 150 Hz and a high scale factor of 9.5 nA/°/s on a test board with a vacuum chamber.The measured angle random walk is 0.145°/√h,and the bias instability is 8.6°/h,showing significant improvement compared to the previous eigenmode AlN BAW gyroscope.The results from this paper prove that with multi-coefficient eigenmode operations,piezoelectric AlN BAW gyroscopes can achieve a noise performance comparable to that of their capacitive counterpart while having the unique advantage of a large open-loop bandwidth and not requiring large DC polarization voltages.

基于深度分子生成模型的类天然产物虚拟筛选库设计（英文）

天然产物在新药研发领域占据着重要的地位。在虚拟筛选库中引入天然产物相关的特征将有助于提升这些化合物库的质量。深度生成模型是一类新兴的全新分子设计方法。在此,我们使用深度分子生成模型构建类天然产物的虚拟筛选库。结果显示,该模型能够生成高天然产物类似性的化合物。另外,该模型也能同时控制天然产物类型性以及合成可及性。基于这些特点,我们可以构造易于合成的类天然产物化合物库,从而提升虚筛库的实际应用价值。

Roles of FERONIA-like receptor genes in regulating grain size and quality in rice

Grain yield and quality are critical factors that determine the value of grain crops.In this study,we analyzed the functions of 12 FERONIA-like receptor(FLR)family members in rice and investigated their effects on grain size and quality.We found that FLR1,FLR2 and FLR8 negatively regulated grain size,and FLR15 positively regulated grain size.flr1 mutants had a higher cell number and an accelerated rate of grain filling compared to wild-type plants,which led to grains with greater widths.A mechanism underlying the regulation of grain size by FLR1 is that FLR1 is associated with OsRac1 Rho-like GTPase,a positive regulator of grain size.Regarding grain quality,the flr1 mutant had a higher percentage of chalkiness compared with wild-type plants,and seeds carrying mutations in flr3 and flr14 had endosperms with white floury cores.To elucidate the possible mechanism underlying this phenomenon,we found that FLR1 was constitutively expressed during endosperm development.RNA-seq analysis identified 2,367 genes that were differentially expressed in the flr1 mutant,including genes involved in starch and sucrose metabolism and carbon fixation.In this study,we identified the roles played by several FLR genes in regulating grain size and quality in rice and provided insights into the molecular mechanism governing the FLR1-mediated regulation of grain size.

Discovery of 4-arylthiophene-3-carboxylic acid as inhibitor of ANO1 and its effect as analgesic agent

Anoctamin 1(ANO1)is a kind of calcium-activated chloride channel involved in nerve depolarization.ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration.In this study,several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening,among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed,synthesized and compound 42(IC;=0.79μmol/L)was finally obtained.Compound 42 selectively inhibited ANO1 without affecting ANO2 and intracellular Ca;concentration.Subsequently,the analgesic effect was investigated by intragastric administration in pain models.Compound 42 significantly attenuated allodynia which was induced by formalin and chronic constriction injury.Through homology modeling and molecular dynamics,the binding site was predicted to be located near the calcium-binding region betweenα6 andα8.Our study validates ANO1 inhibitors having a significant analgesic effect by intragastric administration and also provides selective molecular tools for ANO1-related research.

High-performance and high-thermally stable PSN-PZT piezoelectric ceramics achieved by high-temperature poling

High piezoelectric properties and superior thermal stability are both important indicators of piezoelectric ceramics serving at high temperature.However,since these properties are usually mutually exclusive,high performance and superior thermal stability are hard to achieve simultaneously.Here we report that a high piezoelectricity(d_(33)∼562 pC/N)and superior thermal stability(the variation is within 7%from 20 to 330℃)were both achieved in 0.4 mol%ZnO-doped 0.02Pb(Sb_(1/2)Nb_(1/2))-0.51PbZrO_(3)-0.47PbTiO_(3) by high-temperature poling.Compared with traditional poling method,high-temperature poling method forms a small-sized and highly oriented domain structure,which can effectively improve the piezoelectric and dielectric properties of piezoelectric ceramics.At the same time,the enhanced pinning effect of defect ions and stabilized domain structure due to high-temperature poling also contribute to the superior temperature stability of the piezoelectric and dielectric properties.This work provides an effective method for designing piezoelectric materials with high performance and good temperature stability for high temperature sensor applications.

Coherent Random Lasing Realized in Polymer Vesicles

We have demonstrated the realization of a coherent vesicle random lasing(VRL)from the dye doped azobenzene polymer vesicles self-assembled in the tetrahydrofuran-water system,which contains a double-walled structure:a hydrophilic and hydrophobic part.The effect of the dye and azobenzene polymer concentration on the threshold of random laser has been researched.The threshold of random laser decreases with an increase in the concentration of the pyrromethene 597(PM597)laser and azobenzene polymer.Moreover,the scattering of small size group vesicles is attributed to providing a loop to boost the coherent random laser through the Fourier transform analysis.Due to the vesicles having the similar structure with the cell,the generation of coherent random lasers from vesicles expand random lasers to the biomedicine filed.

天然产物的化学信息学分析及骨架适应症预测(英文)

天然产物是药物发现的重要来源,对天然产物库进行信息学分析有助于加深我们在整体层面上对天然产物的认识,并起到辅助药物设计的作用。本研究收集了较为完整的天然产物库,包含超过220 000个天然产物分子,对其进行分析结果表明天然产物在化学空间上的分布比合成化合物和药物更广,天然产物库的骨架多样性也优于其他化合物库。另外,通过适应症预测模型发现,天然产物骨架在某些适应症例如关节炎、高血压、抗过敏、镇痛上分布较广,然而现有的天然产物来源药物对其利用度并不高,因此我们建议在先导库设计中更多地利用天然产物骨架结构。

Efficient Synthesis of Spiro[furan-3,3＇-indoline] Derivatives via Reactions of Pyridinium Salts with Isatinylidene Acetoacetates

An efficient synthetic procedure for the functionalized spiro[furan-3,3＇-indoline] derivatives was successfully developed by domino reactions of N-phenacylpyridinium bromides or N-ethoxycarbonylmethylenepyridinium bro- mide with isatinylidene acetoacetate in the presence of triethylamine in ethanol at room temperature. The mecha- nism included sequential Michael addition of the in situ generated pyridinium ylide and intramolecular substitution of enolate.

Diastereoselective Synthesis of Arylidene Bis（3-arylamino- acrylates） via One-pot Domino Reactions

The functionalized arylidene bis（3-arylaminoacrylates） were efficiently prepared by FeCl3 catalyzed one-pot domino reactions of primary amines, methyl propiolate and aromatic aldehydes. When isatins were utilized under similar conditions, only 2-oxoindolinyl 3-arylaminoacrylates were obtained in moderate yields. ^1H NMR data and single crystal structures indicated that this reaction has high diastereoselectivity.

Diastereoselective Synthesis of Functionalized Tetrahydropyrimidin-2-thiones via ZnCl2 Promoted One-pot Reactions

In the presence of zinc chloride,the in situ generatedβ-enamino ester from the reaction of morpholine,piperidine and pyrrolidine with methyl propiolate reacted,with aromatic aldehydes and thiourea in ethanol resulting in the functionalized tetrahydropyrimidin-2-thiones in satisfactory yields and with good diastereoselectivity.When aromatic aldehydes bearing electron-withdrawing group were used in the reaction,the 4-hydroxytetrahydropyrimidin-2-thione derivatives were obtained as the main product.

Plug-in Models:A Promising Direction for Molecular Generation

Molecular Generation The molecular generation has emerged as a powerful tool for computer-aided drug design in recent years,as it can explore a large and unknown chemical space and discover novel structures or scaffolds.Furthermore,a candidate compound needs to satisfy multiple criteria,such as target affinity,pharmacokinetics,toxicity,synthetic accessibility,etc.,to pass clinical trials and meet industrial standards.Therefore,multi-objective methods have become a focal point of molecular generation and optimization.Several reviews have been published recently to summarize previous works in molecular generation and categorize them(Table).In this article,we propose a classification scheme based on both the model’s architecture and its practical use,namely,entrenched or plug-in models,especially for multi-objective molecular generation models.We argue that plug-in methods have superior flexibility in both model building and practical use,broader application potential,and higher performance boundaries,and they deserve more attention in the future.

Current Trends and Challenges in Drug-Likeness Prediction:Are They Generalizable and Interpretable?

Importance:Drug-likeness of a compound is an overall assessment of its potential to succeed in clinical trials,and is essential for economizing research expenditures by filtering compounds with unfavorable properties and poor development potential.To this end,a robust drug-likeness prediction method is indispensable.Various approaches,including discriminative rules,statistical models,and machine learning models,have been developed to predict drug-likeness based on physiochemical properties and structural features.Notably,recent advancements in novel deep learning techniques have significantly advanced drug-likeness prediction,especially in classification performance.Highlights:In this review,we addressed the evolving landscape of drug-likeness prediction,with emphasis on methods employing novel deep learning techniques,and highlighted the current challenges in drug-likeness prediction,specifically regarding the aspects of generalization and interpretability.Moreover,we explored potential remedies and outlined promising avenues for future research.Conclusion:Despite the hurdles of generalization and interpretability,novel deep learning techniques have great potential in drug-likeness prediction and are worthy of further research efforts.