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.

Pharmacokinetic Characteristics of Siponimod in Healthy Volunteers and Patients With Multiple Sclerosis: Analyses of Published Clinical Trials.

Objectives: This study aimed to investigate the pharmacokinetic characteristics of siponimod in healthy volunteers and patients with MS based on aggregated data from published clinical trials, and to explore the factors influencing siponimod exposure. Methods: A total of 476 siponimod plasma concentrations aggregated from 28 dosage groups (corresponding to 294 healthy volunteers and 207 patients with MS) were collected from published clinical trials. Population pharmacokinetic (PPK) analysis was performed using a nonlinear, mixed-effect modeling approach. The pharmacokinetic properties of siponimod in healthy volunteers and patients with MS were compared, and the influence of covariates on siponimod exposure was evaluated using both PPK analysis and noncompartmental analysis (NCA). Results: A one-compartment model with first-order absorption and elimination adequately described siponimod pharmacokinetics. The typical population parameter estimates of clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) were 3.17 L/h, 112.70 L, and 0.38 h-1, respectively. An 11.85% lower siponimod clearance was estimated for patients with MS relative to healthy volunteers. Subgroup analyses using NCA assessments revealed that siponimod presented an accumulation index of approximately 2 after multiple administration. Compared with nonobese participants, obese participants had a relatively lower dose-corrected area under the concentration-time curve (AUC0-∞/D) (0.31 vs. 0.42 h/L) and V/F (120.95 vs. 133.75 L), and a relatively higher CL/F (3.25 vs. 3.21 L/h). Participants with CYP2C9*2/*3, *1/*3, and *3/*3 genotypes experienced an increased (1.3- and 3.4-fold, respectively) AUC0-∞/D and a decreased (0.7- and 0.3-fold, respectively) CL/F compared with those in participants with the CYP2C9*1/*1, *1*2, and *2*2 genotypes. Fluconazole combination led to a decrease in CL/F (approximately 0.5 times) and an increase in AUC0-∞/D (approximately 1.3 times). Conclusion: Siponimod pharmacokinetic properties in healthy volunteers and patients with MS were explored using complementary model-based meta-analysis (MBMA) and NCA approaches. A slightly lower siponimod clearance was observed in patients with MS than in healthy volunteers. The dosage regimen, body mass index, CYP2C9 genetic polymorphism and fluconazole combination may had influences on siponimod pharmacokinetics. Such model paves the road to more population-based analyses in different patient populations with MS to quantify the effect of any influencing factors on siponimod pharmacokinetics.

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

Pulmonary embolism after greater saphenous vein ligation and stripping / 中华普通外科杂志

Objective To analyze characteristics and prophylaxis of pulmonary embolism (PE) after greater saphenous vein ligation and stripping.Methods We retrospectively analyzed the clinical characteristics and treatment of 11 inpatients with postoperative PE in Anhui Provincial Hospital and other hospitals from January 2008 to June 2013.Results In this group 6 patients died after failed cardiopulmonary resuscitation (CPR) and other treatments,the mortality was 54.5％.5 patients recovered after anticoagulation,thrombolysis and other treatments.During the process of thrombolysis,floating thrombus was found within the femoral vein in 2 patients and inferior vena cava filter was implanted.After 8-25 months follow-up,all 5 patients were free of difficulty of breathing,chest tightness,chest pain and other symptoms.Among many clinical manifestations,dyspnea (90.9％) was the most common,other clinical manifestations included chest pain (27.3％),syncope (18.2％),sudden death (18.2％).There was no typical triad of dyspnea,chest pain and hemoptysis in these patients.Conclusions Early diagnosis and early treatment of PE are most important to decrease mortality and to improve the prognosis of patients suffering from postoperative PE.

Detailed docking of "phospholipid" biological metabolizing pathway / 中南大学学报(医学版)

OBJECTIVE@#To construct protein functional network according to the physiological process in vivo and functionally based distinct families, to understand biological functions, and to make wise decisions.@*METHODS@#We described here a very effective strategy combining with multiple-docking and protein-ligand binding-affinity fingerprint method to generate bio-functional network and pathway and reveal the protein "unknown" functions and their relationship.@*RESULTS@#Totally 27 sets of proteins and 28 bio-active molecules were used to reconstruct the possible phospholipids metabolic network by computational simulation strategy. The protein-ligand network reconstruction and pathway based drug design showed that the direct interaction investigation might be effective in complex biological system study.@*CONCLUSION@#Even for weak and moderate interactions in the real biology system, the relationship between each other can be achieved by fingerprint analysis based on multiple-docking data. The results of these calculations give valuable insight into the pathway and the function relationship among these proteins. This method can be a very useful tool for protein classification, target selection, and inhibitor design.