Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-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.

Antibody-drug conjugates: Recent advances in payloads

Antibody‒drug conjugates (ADCs), which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing, show great clinical therapeutic value. The ADCs' payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field. An ideal ADC payload should possess sufficient toxicity, low immunogenicity, high stability, and modifiable functional groups. Common ADC payloads include tubulin inhibitors and DNA damaging agents, with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development. However, due to clinical limitations of traditional ADC payloads, such as inadequate efficacy and the development of acquired drug resistance, novel highly efficient payloads with diverse targets and reduced side effects are being developed. This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies, co-crystal structures, and designing strategies, and further discusses the future research directions of ADC payloads. This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy, low toxicity, adequate stability, and abilities to overcome drug resistance.

Polymorphisms of host tropism relating amino acid sites in influenza A virus / 上海预防医学

ObjectiveTo discover and analyze single or several correlative key amino acid sites that influence the host tropism during the influenza A virus （IAV） infection based on complete internal protein gene segments of IAV strains， and to provide evidence for the study of human host-adaptive mutations of IAV. MethodsThe full-length nucleotide sequences of 43 671 IAV strains containing 6 complete internal gene segments were downloaded from the GISAID EpiFluTM database， and 698 human-tropic （HU） and 1 266 avian-tropic （AV） representative strains were included. The consensus coding sequences of the representative strains from the amphitropic category were compared by R script， and the differential amino acid sites and their polymorphisms were then obtained. The multi-site combination analysis of differential sites was conducted with R script. ResultsA total of 49 and 57 conserved differential sites were obtained from the consensus sequence comparison between AV and H1N1 （subtype from HU）， and comparison between AV and H3N2 （another subtype from HU）， separately. 79 and 65 multi-site combinations were found between HU and AV strains through 3 and 4 sites combination analysis， respectively， and a total of 11 conserved sites were involved： site 271 and 684 in PB2； site 336， 486， 581 and 621 in PB1； site 204 and 356 in PA； site 33， 305 and 357 in NP. No eligible differential sites were found in M1 and NS1. ConclusionSeveral conserved amino acid differential sites， between HU and AV strains of IAV， are found in PB2， PB1， PA and NP proteins. Instead of working as single units， these sites may have interactions， forming specific amino acid combinations that determine the host tropism of IAV collectively.

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

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFR simultaneously . Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

Discussions on the ownership and property right structure of public hospitals in China based on new institutionalism / 中华医院管理杂志

Based on the framework of new institutionalism,the paper defined the concept and history of public hospital′s attributes,dividing such hospitals into those built based on poverty alleviation and those on social identity priority.Considering the attributes of the public goods provided by public hospitals,the diversity of their investment,and attributes of their value production process,this paper probed into their property right arrangement.It is emphasized that such hospitals should enhance their key property right feature of public ownership,and on such basis their relationship with government and corporate governance establishment can be discussed.

Effects of dexmedetomidine and propofol on electrocorticography during epileptic resection / 临床麻醉学杂志

Objective To investigate the effects of different doses of dexmedetomidine and propofol on electrocorticography (ECoG)during epileptic resection.Methods One hundred cases of epileptic patients undergoing epileptic resection were randomized into five groups (n=20 cases).Af-ter exposure of the cortex,patients were allocated to propofol group or dexmedetomidine group,the propofol were injected intravenously with different target-controlled-infusion (TCI)concentrations at 1.5 μg/ml (group C1),5.0 μg/ml (group C2)respectively.The dexmedetomidine were injected with a loading dose of 0.5 μg/kg within 1 5 min,then followed by a speed of 0.25 μg·kg-1 ·h-1 (group D1 ),0.5 μg·kg-1 ·h-1 (group D2),and 1.0 μg·kg-1 ·h-1 (group D3)respectively.After 1 5 min of steady infusion,the characteristics of ECoG were recorded.Results Compared with the other four groups,the epileptic spike-wave,αandβwaves were significantly decreased,whileδwave was significantly increased in group C2 (P < 0.05 ).Sometimes burst-suppression-patterns were recorded under propofol. With the dose of dexemedetomidine increasing in groups D1,D2,D3,the epileptic spike-wave,αwave andβwave gradually decreased,while δwave gradually increased (P <0.05).Conclusion Propofol produces dose-dependent inhibition on ECoG,but the epileptic spike-wave still can be differentiated if the plasma con-centration lower than 1.5 μg/ml.Compared with propofol,dexmedetomidine injected with 0.25-0.5 μg· kg-1 ·h-1 ,has few disturbance on epileptic spike-wave differentiation and location during ECoG monito-ring,and is more eligible for epileptic resection anesthesia.

Imaging features of factors related to blood supply from right inferior hepatic artery branches in hepatocellular carcinoma / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To analyze the angiographic features and factors related to the blood supply from right inferior phrenic artery (RIPA) branches in hepatocellular carcinoma (HCC).</p><p><b>METHODS</b>Angiography images of blood supply from RIPA branches and clinical data from patients with HCC who had undergone tmnscatheter arterial chemoembolization in our hospital between 2009 and 2013 were collected for retrospective analysis. Angiographic features of the RIPA branches were assessed for correlation between treatment number, growth pattern, size, tumor location, and rates of blood supplying RIPA branches. Statistical analyses were carried out using chi-square test, t-test, Fisher's exact test and rank sum test.</p><p><b>RESULTS</b>The 140 patients included in the analysis were grouped according to primary HCC (n=63; group A) and recurrent HCC (n=77; group B) and no statistically significant differences were found between the two groups for incidence of each nutrient branch or total number of nutrient branches. In group A, tumor size was associated with number of nutrient branches (P=0.047). There were 32 cases with HCC lesions in the bare area of the liver, and among those 26 of the cases were supplied by the posterior branch of RIPA. Each branch of RIPA showed greater firequency for particular blood supply areas; the anterior branch (n=55) and lateral branch (n=98) fed tumor lesions in segments 7 and 8, the posterior branch (n=98) fed tumor lesions in segments 6 and 7, and the supra-renal branch (n=10) fed tumor lesions in segment 6. The diaphragmatic branch always fed HCC partly located in segments 4 and 8 (n=17). Unique features were present on the digitally subtracted angiography (DSA) image for each nutrient branch and may be useful for distinguishing in clinical examination.</p><p><b>CONCLUSION</b>Cases of primary HCC and recurrent HCC are not distinguishable by incidence of each nutrient branch or total numbers of the nutrient branches. However, tumor size is related to the number of RIPA nutrient branches, and each RIPA nutrient branch shows a dominant preference for certain blood supply areas, with unique features on DSA.</p>

Quantitative Determination of Mangiferin in Rhizoma Belamcandae and Its Substitute of Iris L / 中草药

Mangiferin, one of the active constituents of Rhizoma Belamcandae, in samples of Be-lamcanda chinensis (L.) DC. or its substitute was determined quantitatively by RP-HPLC. The 11 sam-ples collected from different localities for analysis were: 7 rhizomes of wildly grown or cultivated B. chi-nensis, 1 of its leaf and stem, and 3 substitutes (a wildly grown and another commercially available Iristectorum Maxim. and a I. dichotoma Pall. ). Results of the analysis showed that the contents of mangiferinin Rhizoma Belamcandae were significantly higher than that of its substitutes I. tectorum and I. di-chotoma. There were also certain significant differences between samples from different localities (P<0.05), but with no statistically significant difference between the rhizome or leaf and stem, neither be-tween cultivated and wildly grown samples, (P>0.05). The method was proved to be quick, simple andreproducible, and may provide a reliable basis for the quality control and evaluation of B. chinensis.

Identification on Radix Polygoni Multiflori and Radix Cynanchi Auriculati by HPLC fingerprint / 中草药

Objective To establish HPLC fingerprint for the identification of Radix Polygoni Multiflori and Radix Cynanchi Auriculati. Methods Chromatographic fingerprint of Radix Polygoni Multiflori, Radix Cynanchi Auriculati, Radix Polygoni Multiflori Preparata, and "HESHOU WU FEN" was determined by RP-HPLC (DAD) and the gradient elution mode applied in chromatographic separation, data were analysed by Fingerprint Similarity Evaluation Software to compare the similarity of samples. Results Radix Polygoni Multiflori from different samples were of high similarity, but Radix Polygoni Multiflori and Radix Cynanchi Auriculati showed evident difference in fingerprint, and there was difference in fingerprint through processing them. Conclusion HPLC fingerprint method is repeatable and feasible and can be used for the identification of Radix Polygoni Multiflori and Radix Cynanchi Auriculati.

GC-MS Fingerprint of root tuber of Pseudostellaria heterophylla / 中草药

Objective To establish the analytical method for the fingerprint of the volatile components in the root tuber of Pseudostellaria heterophylla by GC-MS and provide the basis for quality assessment of the crude drug.Methods The volatile components in the root tuber of P.heterophylla from different habitats were analyzed and the chromatographic fingerprints were established by GC-MS.The common peaks were determined and the fuzzy cluster was selected to compare the results.Results There were 12 main characteristic components in the volatile components in the root tuber of P.heterophylla.GC-MS Fingerprint of 12 common peaks was established preliminarily.Conclusion The method is reliable and accurate,and can be used for quality control of the root tuber of P.heterophylla.with favourable reproducibility.