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A novel intercalated nanocomposite of mercapto-modified cellulose/bentonite (LCS-BE-SH) was synthesized by high-speed shearing method in one step at room temperature, and was applied to remove Cd from solution and remediate Cd-contaminated soil. Results revealed that cellulose long-chain molecules have intercalated into bentonite nanolayers and interlayer spacing was increased to 1.411 nm, and grafting –SH groups improved adsorption selectivity, which enabled LCS-BE-SH to have distinct capability of Cd adsorption (q max = 147.21 mg/g). Kinetic and thermodynamics showed that Cd adsorption onto LCS-BE-SH was well fitted by pseudo-second-order and Langmuir adsorption isotherm. Characterizations of the adsorbents revealed that synergistic effect of complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH) 2 , CdCO 3) mechanism played a major role in Cd removal. In soil remediation, application of LCS-BE-SH was most effective (67.31 %) in Cd immobilization compared to the control (8.85 %), which reduced exchangeable Cd from 37.03 % to 11.44 %. Meanwhile, soil pH, soil organic matter, available phosphorus, and enzyme activities (catalase, urease, and dehydrogenase) were improved LCS-BE-SH treatment. The main immobilization mechanism in soil included complexation (e.g., CdS, CdO) and precipitation (e.g., Cd(OH) 2 , Cd–Fe-hydroxide). Overall, this work applied a promising approach for Cd removal in aqueous and Cd remediation in soil by using an effective eco-friendly LCS-BE-SH nanocomposites. [Display omitted] • Mercapto-modified cellulose/bentonite intercalated nanocomposite was synthesized. • Cellulose was intercalated into bentonite nanolayers by high-speed shearing methods. • Adsorption selectivity by grafting –SH improved Cd adsorption of nanocomposite. • Such remediation improved Cd immobilization, soil fertility and soil enzyme. • Mechanism of Cd removal in aqueous and remediation of Cd-contaminated soil was revealed. [ABSTRACT FROM AUTHOR]

Summary: Root lodging poses a major threat to maize production, resulting in reduced grain yield and quality, and increased harvest costs.Here, we combined expressional, genetic, and cytological studies to demonstrate a role of ZmYUC2 and ZmYUC4 in regulating gravitropic response of the brace root and lodging resistance in maize.We show that both ZmYUC2 and ZmYUC4 are preferentially expressed in root tips with partially overlapping expression patterns, and the protein products of ZmYUC2 and ZmYUC4 are localized in the cytoplasm and endoplasmic reticulum, respectively. The Zmyuc4 single mutant and Zmyuc2/4 double mutant exhibit enlarged brace root angle compared with the wild‐type plants, with larger brace root angle being observed in the Zmyuc2/4 double mutant. Consistently, the brace root tips of the Zmyuc4 single mutant and Zmyuc2/4 double mutant accumulate less auxin and are defective in proper reallocation of auxin in response to gravi‐stimuli. Furthermore, we show that the Zmyuc4 single mutant and the Zmyuc2/4 double mutant display obviously enhanced root lodging resistance.Our combined results demonstrate that ZmYUC2‐ and ZmYUC4‐mediated local auxin biosynthesis is required for normal gravity response of the brace roots and provide effective targets for breeding root lodging resistant maize cultivars. [ABSTRACT FROM AUTHOR]

Rationale: Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects. Objective: This study was designed to evaluate the anti-nociceptive effects and adverse effects of new combinations of flupirtine (a Kv7 potassium channel opener) and antihistamines (promethazine, fexofenadine) on acute and chronic pain in mice, and the possible mechanisms behind the synergistic analgesic effects were preliminarily investigated. Methods: In acetic acid writhing test, carrageenan-induced inflammatory pain model, and paclitaxel-induced neuropathic pain model, the interaction indexes (γ) between flupirtine and antihistamines were determined by isobolographic analysis. Furthermore, the Kv7 channel blocker XE991 was used to determine whether the effects of single agents and drug combinations on paclitaxel- and carrageenan-induced mechanical allodynia were mediated by Kv7 channels. Finally, hepatotoxicity markers, liver histopathology, and the rotarod test were used to investigate the adverse effects of drugs in combination doses. Results: The interaction indexes of flupirtine-promethazine and flupirtine-fexofenadine in all the above three pain models were lower than 1. The analgesic effects of flupirtine (13 mg/kg), promethazine (5 mg/kg), fexofenadine (20 mg/kg), and their combinations were antagonized significantly by XE991 (3 mg/kg). And the adverse effects of flupirtine and antihistamines in combination doses were not significantly different from the vehicle group. Conclusions: Flupirtine and antihistamines produced synergistic analgesic effects in all the above pain models. The analgesic effects of antihistamines were partially mediated by Kv7/M channels, and the activation of Kv7/M channels may be partly responsible for the synergistic analgesic effects between flupirtine and antihistamines. [ABSTRACT FROM AUTHOR]

Increasing planting density has been adopted as an effective means to increase maize (Zea mays) yield. Competition for light from neighbors can trigger plant shade avoidance syndrome, which includes accelerated flowering. However, the regulatory networks of maize inflorescence development in response to high-density planting remain poorly understood. In this study, we showed that shade-mimicking treatments cause precocious development of the tassels and ears. Comparative transcriptome profiling analyses revealed the enrichment of phytohormone-related genes and transcriptional regulators among the genes co-regulated by developmental progression and simulated shade. Network analysis showed that three homologous Squamosa promoter binding protein (SBP)-like (SPL) transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), individually exhibited connectivity to over 2,400 genes across the V3-to-V9 stages of tassel development. In addition, we showed that the ub2 ub3 double mutant and tsh4 single mutant were almost insensitive to simulated shade treatments. Moreover, we demonstrated that UB2/UB3/TSH4 could directly regulate the expression of Barren inflorescence2 (BIF2) and Zea mays teosinte branched1/cycloidea/proliferating cell factor30 (ZmTCP30). Furthermore, we functionally verified a role of ZmTCP30 in regulating tassel branching and ear development. Our results reveal a UB2/UB3/TSH4-anchored transcriptional regulatory network of maize inflorescence development and provide valuable targets for breeding shade-tolerant maize cultivars. Three homologous SPL transcription factors, Unbranched2 (UB2), Unbranched3 (UB3), and Tasselsheath4 (TSH4), act as a central hub in regulating maize inflorescence development in response to shade. [ABSTRACT FROM AUTHOR]

Here, we explored the possible interaction between duloxetine and SEP-363856 (SEP-856) in depression-related reactions. The results showed that oral administration of duloxetine showed powerful antidepressant-like effects in both the forced swimming test (FST) and the suspension tail test (TST). SEP-856 orally administered alone also exerted an antidepressant-like effect in FST and TST, especially at doses of 0.3, 1, and 10 mg/kg. In addition, duloxetine (15 mg/kg) and SEP-856 (15 mg/kg) both showed antidepressant-like effects in the sucrose preference test (SPT). Most importantly, in the above experiments, compared with duloxetine alone, the simultaneous use of duloxetine and SEP-856 caused a more significant antidepressant-like effect. It is worth noting that doses of drug combination in FST and TST did not change the motor activities of mice in the open-field test (OFT). Thus, duloxetine and SEP-856 seem to play a synergistic role in regulating depression-related behaviors and might be beneficial for refractory depression. [ABSTRACT FROM AUTHOR]

Olanzapine is a commonly used drug in the treatment of schizophrenia, but its clinical application has been restricted by metabolic-related side effects. In order to mitigate the weight gain side effects caused by olanzapine, other drugs with different targets were selected for combined use and evaluated in animal models of schizophrenia. SEP-363856 is a novel psychotropic agent which is under phase III clinical trials for schizophrenia treatment. The aim of the research was to evaluate whether co-administration of olanzapine and SEP-363856 exerts synergistic anti-schizophrenic effects in the apomorphine (APO)-induced climbing test, the MK-801-induced hyperactivity test, and the Morris water maze test, and therefore reduces the weight gain side effects induced by olanzapine. Through isobolographic analysis, the results showed a synergistic interaction in the climbing test; the experimental ED30 (3 mg/kg) was significantly smaller (p < 0.05) than the theoretical ED30 (5 mg/kg). Additionally, such potentiating effects appeared additive in the MK-801 challenge experiment. Co-treatment with an effective dose of olanzapine and a low dose of SEP-363856 reversed MK-801-induced cognitive impairment symptoms in mice. Moreover, combination treatment with olanzapine and SEP-363856 controls sustained weight gain in mice with chronic exposure to olanzapine. These results support further clinical trials to test the effectiveness of co-treatment of olanzapine and SEP-363856 for controlling symptoms and weight gain in patients with schizophrenia during antipsychotic treatments. [ABSTRACT FROM AUTHOR]

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ 1 R) receptors are reported. Compound 23 exhibited good affinity to σ 1 R (K i = 44.7 ± 7.05 nM) and high selectivity to σ 2 R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED 50 = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED 50 = 5.23 mg/kg)). We obtained new dual ligands that might serve as starting points for preparing targeted tools. Furthermore, 23 may be a useful chemical probe for understanding more fully analgesic effects associated with MOR agonism and σ 1 R antagonism. • A series of thiophenpiperazine amide derivatives were synthesised. • The structure activity relationships of the targeted compounds were summarised. • Selected compounds exhibited the desirable potent σ 1 R antagonism and MOR agonism profiles. • The most active compound exerted potent analgesic activity in in vivo animal model. [ABSTRACT FROM AUTHOR]

Abstract: Current biology is experiencing transformation in logic or philosophy that forces us to reevaluate the concept of cell, tissue or entire organism as a collection of individual components. Systems biology that aims at understanding biological system at the systems level is an emerging research area, which involves interdisciplinary collaborations of life sciences, computational and mathematical sciences, systems engineering, and analytical technology, etc. For analytical chemistry, developing innovative methods to meet the requirement of systems biology represents new challenges as also opportunities and responsibility. In this review, systems biology-oriented micro-separation technologies are introduced for comprehensive profiling of genome, proteome and metabolome, characterization of biomolecules interaction and single cell analysis such as capillary electrophoresis, ultra-thin layer gel electrophoresis, micro-column liquid chromatography, and their multidimensional combinations, parallel integrations, microfabricated formats, and nano technology involvement. Future challenges and directions are also suggested. [Copyright &y& Elsevier]

Oxycodone is one of the most prescribed narcotic medications for the treatment of moderate to severe pain in clinical practice. During long-term stability studies of oxycodone hydrochloride for injection performed as per ICH Q1A (R2) guidelines, an unknown degradation product, impurity-I, increased over time and reached a level of 0.21% after 24 months, based on the results of HPLC analysis. The observed impurity was preliminarily characterized as an oxycodone aldol dimer by using two-dimensional (2D) liquid chromatography (LC) coupled with quadrupole time-of-flight mass spectrometry (QTOF MS/MS) analysis. Impurity-I was synthesized and its molecular structure confirmed based on detailed analysis of 1D-NMR (1H, 13C, and DEPT) and 2D-NMR (1H–1H COSY, HSQC, and HMBC) spectroscopy data. The plausible mechanism for the formation of impurity-I was an aldol condensation reaction under weakly acidic conditions. In addition, the potential toxicity of impurity-I was assessed by in silico toxicity predictions using the TOPKAT software. [ABSTRACT FROM AUTHOR]

Different solid forms possess various physicochemical properties, which can significantly affect the stability, bioavailability, and manufacturability of the final product. DP-VPA, a complex of 1-stearoyl-2-valproyl- sn -glycero-3-phosphatidylcholine (DP-VPA-C 18) and 1-palmitoyl-2-valproyl- sn -glycero-3-phosphatidylcholine (DP-VPA-C 16), is currently under development as an antiepileptic drug. DP-VPA-C 16 and DP-VPA-C 18 crystallize together in solid solution forms. The solid forms of DP-VPA solid solution were studied herein. Powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), dynamic vapor sorption (DVS) and optical microscopy were used to characterize the different crystalline forms, known as polymorphs. The physicochemical properties, including hygroscopicity, thermodynamic behavior, and relative stability, of each form were investigated. DVS analysis showed that DP-VPA solid solution reduced the hygroscopicity of DP-VPA-C 16. The relative humidity stability study revealed that Forms A and B are relatively stable, while Forms A-1, B-1, C and D are highly unstable under natural humidity. Further analysis revealed that Form A transforms into Form B through milling. Given the physicochemical properties of the available physical forms, Form B may be the optimal form for the formulation and development of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

• A series of lactam derivatives were designed and synthesized. • Compound 11 shown to be potent and selective H 3 receptor ligands. • Compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. The synthesis and H 3 receptor ligand of a new series of lactam derivatives are reported. The new compounds were evaluated in vitro in H 3 and H 1 receptor-binding assays. The structure-activity relationship led us to the promising derivative 2-methyl-7-(3-morpholinopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (11). The compound with highest affinity and greatest selectivity were further profiled, In addition, compound 11 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 11 could be a potent candidate for pain treatment. [ABSTRACT FROM AUTHOR]

Introduction: The relationship of total cholesterol (TC) or triglyceride (TG) to diabetic retinopathy (DR) has proven difficult to determine. In addition, there is no report of any study of the correlation between the TC/TG ratio and DR. This study was therefore undertaken to investigate the relationship between the TC/TG ratio and DR in Chinese adults with type 2 diabetes mellitus. Methods: A community-based study was conducted from August to October 2014 in Fengyutan, Shenyang, China. DR was assessed based on the modified Airlie House classification of DR. Multivariable logistic regression models were used to evaluate the association between the TC/TG ratio and the presence of DR. Results: Among the 420 diabetic participants in the study (157 men; mean (SD) age 61.7 (10.0) years), 76 (18.1%) presented with DR. When the TC/TG ratio was analyzed categorically, participants with T2DM in tertile 2 (i.e., TC/TG 2.91–4.00) were more likely (OR 2.01; 95% CI 1.01–3.99) to suffer from DR than patients in tertile 1 (i.e., TC/TG < 2.91) in multivariable models. Similarly, participants in tertile 3 (TC/TG > 4.00) were more likely (OR 2.59; 95% CI 1.11–3.14; P = 0.011) to suffer from DR than patients in tertile 1. This association persisted when the TC/TG ratio was analyzed continuously (P = 0.014). Conclusion: We found a novel positive association between TC/TG ratio and presence of DR in Chinese individuals with T2DM. Although longitudinal data are needed, this finding contributes to the accumulating evidence that a high TC/TG ratio may be implicated in DR. [ABSTRACT FROM AUTHOR]

Olanzapine is a marketed antipsychotic agent for treatment of both positive and negative symptoms of schizophrenia. The chemical synthesis of olanzapine drug substance involved the reaction of thienobenzodiazepine hydrochloride with N -methylpiperazine. During the manufacture of olanzapine, two unknown impurities were present in pilot batches in the range of 0.08–0.22% based upon HPLC analysis. These unknown impurities were enriched from the mother liquor of reaction by preparative HPLC, and characterized by UV, FT-IR, LC–MS/TOF, 1D-NMR ( 1 H, 13 C, DEPT), 2D-NMR ( 1 H- 1 H COSY, HSQC, HMBC, ROESY) and single-crystal X-ray diffraction analysis. Based on the complete spectral analysis and knowledge of the synthetic route of olanzapine, these two new impurities were identified as 2-methyl-4-(4-methyl piperazin-1-yl)-10-((methylthio)methyl)-thieno[2,3 -b ][1,5] benzodiazepine (impurity-I) and 10-(3-(1H-benzo[d]imidazol-2-yl)-5-methylthiophen-2-yl)-2-methyl-4-(4-methyl piperazin-1-yl)-thieno[2,3 -b ][1,5]benzodiazepine (impurity-II). Finally, prospects to the formation and controlling of impurity-I and II were discussed in detail. [ABSTRACT FROM AUTHOR]

[Display omitted] • Twenty-three novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. • Compounds 13–15 showed potent hypnotic potency and higher therapeutic indexes than propanidid or propofol in rabbits. • The recovery time of compounds 13–15 was shorter than that of propanidid or propofol in rabbits. In this work, a series of novel heterocyclic 2-phenylacetate derivatives were designed and synthesized as water-soluble and rapid recovery hypnotic agents. After introducing heterocyclic ring to the amide group of propanidid, the obtained propanidid derivatives showed greatly improved hydrophilicity and good anesthetic activity. In three animal experiments (mice, rats, and rabbits), compounds 13–15 showed potent hypnotic potency (HD 50 = 7.6, 6.5, 7.4 mg/kg in rabbits, respectively) and higher therapeutic indexes (TI = 17.3, 16.6, 15.2 in rabbits, respectively) than propanidid (TI = 14.7 in rabbits) or propofol (TI = 5.4 in rabbits). Moreover, the recovery time of compounds 13–15 (time to walk, 96.6, 79.6, 81.4 s in rabbits, respectively) were shorter than that of propanidid (124.5 s in rabbits) or propofol (425.3 s in rabbits). The experimental results suggested the potential of compounds 13–15 as water-soluble anesthetics with rapid recovery profile. [ABSTRACT FROM AUTHOR]

In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D 2 , K i = 0.5 ± 0.07 nM; 5-HT 1A , K i = 5.9 ± 0.8 nM; 5-HT 2A , K i = 0.3 ± 0.01 nM; 5-HT 6 , K i = 0.5 ± 0.04 nM) and combined with low affinities for the H 1 , 5-HT 2C , and adrenergic α 1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia. [ABSTRACT FROM AUTHOR]

To develop safer and potent analgesics, we designed, synthesized, and evaluated a new series of benzylaminofentanyl derivates as bifunctional μ opioid receptor (MOR) and σ 1 receptor (σ 1 R) ligands. Compound 68 (Tao-191) showed desirable MOR agonism (K i = 6.5 nΜ; EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro , and exerted powerful analgesic effects in the abdominal constriction test (ED 50 = 0.32 mg/kg, in mice), formalin-induced pain test (phase II, ED 50 = 2.26 mg/kg, in rats), and paclitaxel-induced neuropathic pain model (ED 50 = 0.30 mg/kg, in mice). The contributions of MOR and σ 1 R to its antinociceptive effect were verified by combined administration with the MOR antagonist naloxone and the σ 1 R agonist PRE-084, respectively. At equianalgesic doses, compound 68 induced fewer MOR-related side effects—including physical and psychological dependence, respiratory depression, constipation, and acute hyperlocomotion—than fentanyl. The results provide a rationale for further exploration of the action and safety of dual MOR/σ 1 R ligands as a promising avenue for the development of potent and safe analgesics. [Display omitted] • A series of benzylaminofentanyl derivates were synthesized as bifunctional MOR/σ 1 R ligands to develop safer analgesics. • Compound 68 showed desirable MOR agonism (EC 50 = 48.5 nΜ, E max = 66.3%) and σ 1 R antagonism (K i = 35.7 nM) in vitro. • Compound 68 exerted powerful analgesic effects in abdominal constriction test and formalin-induced pain test in rodents. • At equianalgesic doses, compound 68 induced fewer MOR-related side effects than fentanyl in mice. [ABSTRACT FROM AUTHOR]

A new water-soluble benzodiazepine derivative, CNS 7056 (named as remimazolam), has been undergoing many reactions in recent years to provide an intravenous agent with a predictable fast-onset, short duration of action, and rapid recovery profile. Based on the structure of CNS 7056 with proven activity, seven new CNS 7056 derivatives were designed, and their sedative activities upon mouse, rats, and rabbits were examined. Sedative activities of EL -001˜007 were screened. The results indicated that the shorter the side chain at C3 position is, the higher the sedative activity is. EL -001 was chosen as the optimal compound for studies of ED50, LD50, latency to LRR and the duration of LRR, and its anesthetic activity was compared with that of CNS 7056 in rats and rabbits. Studies showed that EL -001 is a potent sedative in rodent and lagomorpha, with a short duration of action. Compared with CNS 7056, EL -001 has a shorter period of induction despite a slightly longer sedative duration and recovery time. [ABSTRACT FROM AUTHOR]

Human α7 nicotinic acetylcholine receptor (nAChR) is a promising therapeutic target for the treatment of schizophrenia accompanied with cognitive impairment. Herein, we report the synthesis and agonistic activities of a series of indolizine derivatives targeting to α7 nAChR. The results show that all synthesized compounds have affinity to α7 nAChR and some give strong agonistic activity, particularly most active agonists show higher potency than control EVP-6124. The docking and structure–activity relationship studies provide insights to develop more potent novel α7 nAChR agonists. [ABSTRACT FROM AUTHOR]

Olanzapine (OLZ) is a second-generation atypical anti-schizophrenia drug, and it had been developed into various formulations, including immediate release and long-acting formulations. Specific solubility properties of OLZ are very important to design formulations for specific administration. In present work, two novel cocrystals of OLZ were synthesized and characterized (OLZ-KAE·0.75EA·0.25H 2 O, OLZ-ORC, KAE = kaempferol, ORC = orcinol). Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), synchronous thermal analysis and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) were used to characterize the structure of the cocrystals. Hirshfeld surface analysis was used to understand intermolecular interactions in cocrystals. In OLZ-KAE·0.75EA·0.25H 2 O cocrystal, the ethyl acetate (EA) and H 2 O exist as channel crystalline solvate, and they can easily escape from the lattice channel. Powder dissolution study showed that OLZ-ORC improved the dissolution rate of OLZ in PH 6.8 phosphate buffer. However, OLZ-KAE·0.75EA·0.25H 2 O and its desolvation product decreased the dissolution rate of OLZ, and the release rate kept sustained and stable, which was very suitable for sustained release and long-acting muscle injection formulations. • Two novel cocrystals of olanzapine with kaempferol or orcinol were synthesized and characterized. • The desolvation of olanzapine with kaempferol cocrystal were studied by variable-temperature X-ray powder diffraction. • Cocrystal of olanzapine with kaempferol decreased the dissolution rate of olanzapine. • Cocrystal of olanzapine with orcinol enhanced the dissolution rate of olanzapine. [Display omitted] [ABSTRACT FROM AUTHOR]

We report the synthesis of novel, potentially hypnotic fluorine-substituted phenyl acetate derivatives. We describe the structure–activity relationship that led us to the promising derivative: ethyl 2-(4-(2-(diethylamino)-2-oxoethoxy)-5-ethoxy-2-fluorophenyl) acetate ( 55 ). The unique pharmacological features of compound 55 are its relatively high affinity for the GABA A receptor, together with a unique affinity for the NMDA receptor, different to propanidid and AZD3043. In animal models, compound 55 showed stronger hypnotic potency and longer duration of LORR than propanidid and AZD3043, but also maintained a rapid recovery time to walking and behavioral recovery. In particular, compound 55 displayed reflex depression during infusion. [ABSTRACT FROM AUTHOR]

Thediscovery and synthesis of a new series of pyrimidines as potentsigma-1 receptor (σ1R) antagonists, associated withpharmacological antineuropathic pain activity, are the focus of thisarticle. The new compounds were evaluated in vitro in σ-1 andσ-2 receptor binding assays. The nature of the pyrimidine scaffoldwas crucial for activity, and a basic amine was shown to be necessaryaccording to the known pharmacophoric model. The most promising derivativewas 5-chloro-2-(4-chlorophenyl)-4-methyl-6-(3-(piperidin-1-yl)propoxy)pyrimidine(137), which exhibited a high binding affinity to σ1R receptor (Kiσ1= 1.06 nM) and good σ-1/2 selectivity (1344-fold). In in vivotests, compound 137exerted dose-dependent antinociceptiveeffects in mice formalin model and rats CCI models of neuropathicpain. In addition, no motor impairments were found in rotarod tests;acceptable pharmacokinetic properties were also noted. These datasuggest compound 137may constitute a novel class ofdrugs for the treatment of neuropathic pain. [ABSTRACT FROM AUTHOR]

[Display omitted] • Eighteen phenylpiperazine-phenylacetate derivatives with hypnotic potencies were synthesized. • Compound 10 showed apparently rapid recovery and higher safety than propanidid in animal models. • Compound 10 had a greater binding affinity for the GABA A receptor and a lower affinity for the off-target receptors. In this paper, we designed and synthesized a series of novel phenylpiperazine-phenylacetate derivatives as rapid recovery hypnotic agents. The best compound 10 had relatively high affinity for the GABA A receptor and low affinity for thirteen other off-target receptors. In three animal models (mice, rats, and rabbits), compound 10 exerted potent hypnotic effects (HD 50 = 5.2 mg/kg in rabbits), comparable duration of the loss of righting reflex (LORR), and significant shorter recovery time (time to walk) than propanidid. Furthermore, compound 10 (TI = 18.1) showed higher safety profile than propanidid (TI = 14.7) in rabbits. Above results suggested that compound 10 may have predictable and rapid recovery profile in anesthesia. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and sigma-1 receptor (σ 1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure–activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1-(4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (K i σ 1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment. [Copyright &y& Elsevier]

Background: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. Methodology/Principal Findings: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. Conclusions/Significance: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness. [ABSTRACT FROM AUTHOR]

Abstract: A series of benzoxazole/benzothiazole-2,3-dihydrobenzo[b][1,4]dioxine derivatives (5a–5d and 8a–8j) was synthesized. Compounds were evaluated for binding affinities at the 5-HT1A and 5-HT2A receptors. Antidepressant activities of the compounds were screened using the forced swimming test (FST) and the tail suspension test (TST). The results indicated that the compounds exhibited high affinities for the 5-HT1A and 5-HT2A receptors and showed a marked antidepressant-like activity. Compound 8g exhibited high affinities for the 5-HT1A (K i =17nM) and 5-HT2A (K i =0.71nM) receptors; it also produced a decrease of the immobility time and exhibited potent antidepressant-like effects in the FST and TST in mice. [Copyright &y& Elsevier]

Abstract: In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT1A, 5-HT2A receptors, together with a low affinity for H1 receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine. [Copyright &y& Elsevier]

Palbociclib (PAL) is an effective anti-breast cancer drug, but its use has been partly restricted due to poor bioavailability (resulting from extremely low water solubility) and serious adverse reactions. In this study, two cocrystals of PAL with resorcinol (RES) or orcinol (ORC) were prepared by evaporation crystallization to enhance their solubility. The cocrystals were characterized by single crystal X-ray diffraction, Hirshfeld surface analysis, powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, Fourier transform infrared and scanning electron microscopy. The intrinsic dissolution rates of the PAL cocrystals were determined in three different dissolution media (pH 1.0, pH 4.5 and pH 6.8), and both cocrystals showed improved dissolution rates at pH 1.0 and pH 6.8 in comparison to the parent drug. In addition, the cocrystals increased the solubility of PAL at pH 6.8 by 2–3 times and showed good stabilities in both the accelerated stability testing and stress testing. The PAL-RES cocrystal also exhibited an improved relative bioavailability (1.24 times) than PAL in vivo pharmacokinetics in rats. Moreover, the in vitro cytotoxicity assay of PAL-RES showed an increased IC50 value for normal cells, suggesting a better biosafety profile than PAL. Co-crystallization may represent a promising strategy for improving the physicochemical properties of PAL with better pharmacokinetics. [ABSTRACT FROM AUTHOR]

Here, we describe the optimization, synthesis, and associated pharmacological analgesic activities of a new series of bifunctional piperidinamide derivatives as sigma-1 receptor (σ 1 R) antagonists and mu opioid receptor (MOR) agonists. The new compounds were evaluated in vitro in σ 1 R and MOR binding assays. The most promising compound 114 (also called HKC-126), showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. Compound 114 showed powerful dose-dependent analgesic effects in the acetic acid writhing test, formalin test, hot plate test, and chronic constriction injury (CCI) neuropathic pain model. In contrast to an equianalgesic dose of fentanyl, compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence, and sedation. Lastly, the pharmacokinetic properties of this drug were also acceptable, and these results suggest that compound 114 , as a mixed σ 1 R/MOR ligand, has potential for treating neuropathic pain. [Display omitted] 1. A new series of bifunctional piperidinamide derivatives were synthesized and evaluated biological activity. 2. Compound 114 showed superior affinities for σ 1 R and MOR and good selectivity to additional receptors related to pain. 3. Compound 114 showed powerful dose-dependent analgesic effects in different models. 4. Compound 114 produced fewer opioid-like side effects, such as reward liability, respiratory depression, physical dependence and sedation than fentanyl at an equianalgesic dose. [ABSTRACT FROM AUTHOR]

Opioid analgesics are highly effective painkillers for the treatment of moderate or severe pain, but they are associated with a number of undesirable adverse effects, including the development of tolerance, addiction, constipation and life-threatening respiratory depression. The development of new and safer analgesics with innovative mechanisms of action, which can enhance the efficacy in comparison to available treatments and reduce their side effects, is urgently needed. The sigma-1 receptor (σ 1 R), a unique Ca2+-sensing chaperone protein, is expressed throughout pain-modulating tissues and affects neurotransmission by interacting with different protein partners, including molecular targets that participate in nociceptive signalling, such as the μ-opioid receptor (MOR), N -methyl- d - aspartate receptor (NMDAR) and cannabinoid 1 receptor (CB 1 R). Overwhelming pharmacological and genetic evidence indicates that σ 1 R antagonists induce anti-hypersensitive effects in sensitising pain conditions (e.g. chemically induced, inflammatory and neuropathic pain) and enhance opioid analgesia but not opioid-mediated detrimental effects. It has been suggested that balanced modulation of MORs and σ 1 Rs may improve both the therapeutic efficacy and safety of opioids. This review summarises the functional profiles of ligands with mixed MOR agonist and σ 1 R antagonist activities and highlights their therapeutic potentials for pain management. Dual MOR agonism/σ 1 R antagonism represents a promising avenue for the development of potent and safer analgesics. [Display omitted] • σ 1 R antagonists exhibit anti-hypersensitive effects in sensitising pain conditions. • σ 1 R antagonists enhance opioid analgesia but not opioid-mediated unwanted effects. • Bifunctional MOR and σ 1 R ligands possess wider therapeutic window with fewer adverse effects. • Representative ligands with MOR agonist and σ 1 R antagonist activities were summarised. • Dual MOR-agonism/σ 1 R-antagonism represents a promising avenue for the development of potent and safer analgesics. [ABSTRACT FROM AUTHOR]

Thediscovery and synthesis of potential and novel antipsychoticcoumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1Aand 5-HT2Areceptor properties, are the focus of the present article. The most-promisingderivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possessesunique pharmacological features, including high affinity for dopamineD2and D3and serotonin 5-HT1Aand5-HT2Areceptors. Moreover, it possesses low affinity for5-HT2Cand H1receptors (to reduce the riskof obesity associated with chronic treatment) and hERG channels (toreduce the incidence of torsade des pointes). In animal models, compound 17minhibited apomorphine-induced climbing behavior, MK-801-inducedhyperactivity, and the conditioned avoidance response without observablecatalepsy at the highest dose tested. Further, fewer preclinical adverseevents were noted with 17mcompared with risperidonein assays that measured prolactin secretion and weight gain. Acceptablepharmacokinetic properties were also noted with 17m.Taken together, 17mmay constitute a novel class of drugsfor the treatment of schizophrenia. [ABSTRACT FROM AUTHOR]

[Display omitted] • Isolation, identification and characterization of an unknown process-related impurity (impurity-I) in sugammadex sodium. • Structural elucidation of this new impurity has been confirmed by LC–MS/QTOF, 1D-NMR and 2D-NMR data. • Prospects to the formation and controlling of impurity-I have been discussed in detail. Sugammadex sodium is the first selective relaxant binding agent (SRBA) indicated for reversal of neuromuscular blockade induced by rocuronium or vecuronium during surgery. The chemical synthesis of sugammadex involved the nucleophilic substitution reaction between 6-per-deoxy-6-per-halo-γ-cyclodextrin and 3-mercaptopropionic acid under basic conditions. During the manufacture of sugammadex sodium, an unknown process-related impurity was observed in pilot batches in the range of 0.21–1.9 % based upon HPLC analysis. The same impurity was also detected in commercial Bridion® samples at the levels of more than 0.1 %. Thus this unknown impurity was enriched from the mother liquor of reaction by preparative HPLC and characterized by LC–MS/QTOF, 1D-NMR (1H, 13C, DEPTQ) and 2D-NMR (1H-1H COSY, TOCSY, HSQC, HMBC, NOESY) techniques. Based on spectroscopic analysis and the synthetic route of sugammadex sodium, this new impurity was identified as monocyanoethyl sugammadex (impurity-I). The prospects to the formation mechanism and control strategy of impurity-I were discussed in detail. Moreover, the toxicological properties of impurity-I were evaluated using ADMET Predictor® software. [ABSTRACT FROM AUTHOR]

In vitro (K i , nM): D 2 , 10.5; D 3 , 9.6; 5-HT 1A , 5.6; 5-HT 2A , 8.4; H 3 , 14.0; 5-HT 6 , 141.0; H 1 , 968.3; 5-HT 2C , 610.4; α 1 , 438.2. In vivo (ED 50 , mg/Kg): APO, 0.09; MK-801, 0.2; CAT, 32.0; CAR, 1.3. Pharmacokinetic: t 1/2 , 5.0 h; F%, 24.0. [Display omitted] • A series novel benzoisoxazoleylpiperidine derivative was designed and synthesized. • Compound 4w shown showed highest affinities to D 2 , 5-HT 1A , 5-HT 2A and H 3 receptors. • Compound 4w has alleviated the schizophrenia-like symptoms and reduced side effects. • Compound 4w showed favorable pharmacokinetic profile. A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H 3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D 2 , D 3 , 5-HT 1A , 5-HT 2A and H 3 , a moderate affinity for 5-HT 6 , negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT 2C , adrenergic α 1 and H 1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug. [ABSTRACT FROM AUTHOR]

Cocrystallization is an important route to tuning the solubility in drugs development, including improving and reducing. Five cocrystals of aripiprazole (ARI) with resveratrol (RSV) and kaempferol (KAE), ARI-RSV, ARI2-RSV1·MeOH, ARI-KAE, ARI-KAE·EtOH, ARI-KAE·IPA, were synthesized and characterized. The single crystal of ARI2-RSV1·MeOH, ARI-KAE·EtOH, and ARI-KAE·IPA were analyzed by single crystal X-ray diffraction (SCXRD). The SCXRD showed multiple intermolecular interactions between API and the coformers, including hydrogen bond, halogen bond, and π-π interactions. Dissolution rate of the two nonsolvate ARI-RSV and ARI-KAE cocrystals were investigated through powder dissolution experiment in pH = 4.0 acetate buffer and pH = 6.8 phosphate buffer. The result showed that RSV could reduce the dissolution rate and solubility of ARI in both medium through cocrystallization. However, KAE improved the dissolution rate and solubility of ARI in pH = 4.0 medium, on the contrary, the two solubility indicators of ARI were both reduced for ARI-KAE cocrystal. [ABSTRACT FROM AUTHOR]

In this study, a series of novel Isoquinolinone derivatives were synthesized as potential multi-target antipsychotics. Among these, compound 13 showed high affinity for dopamine D 2 and serotonin 5-HT 1A , 5-HT 2A , 5-HT 6 , and 5-HT 7 receptors, showed low affinity for off-target receptors (5-HT 2C , H 1 , and α 1), and negligible effects on ether-a-gogo-related gene (hERG; i.e., reduced QT interval prolongation). An animal behavioral study revealed that compound 13 reversed APO-induced hyperlocomotion, MK-801-induced hyperactivity, an induced head twitch. Moreover, compound 13 exhibited a high threshold for acute toxicity, a lack of tendency to induce catalepsy, and did not cause prolactin secretion or weight gain when compared to risperidone. Furthermore, in the forced swim test, tail suspension test, and novel object recognition test, treatment with compound 13 resulted in improvements in depression and cognitive impairment. In addition, compound 13 had a favorable pharmacokinetic profile in rats. Thus, the antipsychotic drug-like effects of compound 13 indicate that it may be useful for developing a novel class of drugs for the treatment of schizophrenia. Image 1 [ABSTRACT FROM AUTHOR]

Zinc pyrithione (ZPT) is an extensively used microbicidal agent and its toxicity to multiple organs has been gradually recognized. However, details of the mechanism of ZPT toxicity are lacking and profile studies at metabolic level are still greatly limited. In this work we investigated the effects of ZPT on metabolic pathways of zebrafish liver after twenty-one days of exposure. Our integrated approach was underpinned by gas chromatography coupled with mass spectroscopy (GC-MS) and liver function analysis. Metabolomic profiles were generated from the livers of ZPT-treated zebrafish and 172 significantly altered metabolite peaks were detected. As a result, ZPT caused altered perturbation of metabolic pathways in male and female zebrafish liver. Moreover, ZPT induced the liver injury with the changes of the metabolites 2,4-diaminobutyric acid (2,4-DABA) with significant distinction between male and female zebrafish. ZPT caused gender-differentiated liver metabolic changes associated with the disruption of glycogenolysis and glycolysis metabolism, purine and pyrimidine metabolism, oxidative phosphorylation, arginine biosynthesis, and amino acid metabolism. Conclusively, exposure of ZPT may result in gender-differentiated metabolic abnormalities of adult zebrafish with induced hepatotoxicity. • Toxic responses of zebrafish to ZPT reveal gender-differentiated metabolic hepatotoxicity. • ZPT altered gender-differentiated disruption of glycogenolysis and glycolysis metabolism, etc.. • 2, 4-diaminobutyric acid could induce liver injury with significant difference between male and female zebrafish. [ABSTRACT FROM AUTHOR]

The design of a series of novel flavone derivatives was synthesized as potential broad-spectrum antipsychotics by using multi-receptor affinity strategy between dopamine receptors and serotonin receptors. Among them, 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl) piperidin- 1-yl) butoxy)-2,2-dimethylchroman-4-one (6j) exhibited a promising preclinical profile. Compound 6j not only showed high affinity for dopamine D2, D3, and serotonin 5-HT1A, 5-HT2A receptors, but was also endowed with low to moderate activities on 5-HT2C, α1, and H1 receptors, indicating a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In vivo behavioral studies suggested that 6j has favorable effects in alleviating the schizophrenia-like symptoms without causing catalepsy. Taken together, compound 6j has the potential to be further developed as a novel atypical antipsychotic. [ABSTRACT FROM AUTHOR]

A potent antipsychotic drug candidate, 7-(4-(4-(6-fluorobenzo[ d ]-isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro -2H-chromen-2-one mesylate(CY611), with good in vitro and in vivo antipsychotic effects was investigated for preformulation evaluation by crystallography methods. Three anhydrous polymorphs(Form I–III), a monohydrate(Form IV), and a NMP solvate(Form V) were discovered and characterized by powder X-ray diffraction, thermal analysis, attenuated total reflection-fourier transform infrared spectroscopy and scanning electron microscopy. Form I, monohydrate Form IV, and a NMP solvate Form V of the drug candidate were isolated, and their structures were determined by single crystal X-ray diffraction. IDR and relative stability experiment were performed. Although Form II has the fastest release rate in water, it easy transformed to monohydrate which has the lowest release rate. In vivo pharmacokinetic study showed that the Form III has the highest bioavailability at 35.4%. Considering the balance between the physicochemical properties, bioavailability and manufacturability of the available polymorphs, Form III may be the optimal form candidate for the eventual formulation. [ABSTRACT FROM AUTHOR]

We designed and synthesized a novel series of piperidine propionamide derivatives as potent sigma-1 (σ 1) receptor antagonists and mu (μ) opioid receptor agonists, and measured their affinity for σ 1 and μ receptors in vitro through binding assays. The basic scaffold of the new compounds contained a 4-substituted piperidine ring and N-aryl propionamide. Compound 44, N-(2-(4-(4-fluorobenzyl) piperidin-1-yl) ethyl)-N-(4-methoxy-phenyl) propionamide, showed the highest affinity for σ 1 receptor (K i σ 1 = 1.86 nM) and μ receptor (K i μ = 2.1 nM). It exhibited potent analgesic activity in the formalin test (ED 50 = 15.1 ± 1.67 mg/kg) and had equivalent analgesic effects to S1RA (σ 1 antagonist) in a CCI model. Therefore, Compound 44, which has mixed σ 1 /μ receptor profiles, may be a potential candidate for treating neuropathic pain. Image 1 • A new series of piperidine propionamide derivatives was designed and synthesized. • Compound 44 showed highest affinities to σ 1 receptor and μ receptor with mixed σ 1 /μ receptor profiles. • Compound 44 performed a dose-dependent analgesic effect in the formalin test. • Compound 44 performed equivalent analgesic effect with S1RA. [ABSTRACT FROM AUTHOR]

The α7 nicotinic acetylcholine receptor (α7 nAChR) has emerged as a promising therapeutic target for schizophrenia. In our previous work, a novel series of α7-nAChR agonists bearing scaffold of indolizine were discovered. To explore the effect of aromaticity on the activity and find more active agents, herein, fused heterocyclic carboxamide derivatives were designed and synthesized in this study. Based on the evaluation by two-electrode voltage clamp in Xenopus oocytes, 27 of the synthesized compounds showed obvious agonism of α7 nAChR. Particularly, compounds 10a and 10e showed significantly higher E max than EVP-6124. The result illustrated the importance of aromaticity to the activity of agonism. Compound 10a , which showed EC 50 of 1.88 μM and E max of 72.4%, was further characterized comprehensively, including co-application with type II positive allosteric modulator PNU-120596, selectivity with other closely related ligand-gated ion channel, etc. The results showed that 10a showed moderate selectivity over other subtypes such as α4β2 and α3β4 nAChR. 10a evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. The analysis of binding mode and understanding of structure-activity relationship provided insights to develop more potent novel α7-nAChR agonists. Schematic representation of the designed fused heterocyclic carboxamide derivatives. Image 1 • Novel fused heterocyclic carboxamide α7 agonists were designed and synthesized. • Compound 10a and 10e showed significant efficacy and higher E max than EVP-6124. • 10a evoked α7-like currents and enhanced in the presence of the α7 PAM. • The aromaticity favored the activity of agonism. [ABSTRACT FROM AUTHOR]

GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique. [ABSTRACT FROM AUTHOR]

Compound (I) shows high affinity for dopamine D2 and D3, serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors with a low affinity for the H1 receptor. [ABSTRACT FROM AUTHOR]