Metal-Free, Adjustable, and Recyclable Catalytic Systems for the Construction of C-C Bonds by Activating Propargylic Alcohols.

Pyrano[3,2-c]coumarin derivatives and C3-substituted 4-hydroxycoumarins as important skeletal structures of active natural products and pharmaceutically relevant molecules have received increasing attention. However, developing an adjustable system for selectively synthesizing them is still a challenging task. Herein, sulfonic acid-functionalized ionic liquid was successfully used as the catalyst for the alkylation of 4-hydroxycoumarin derivatives with secondary aromatic propargylic alcohols using dimethyl carbonate as the green solvent, giving up to 98% yield. On the other hand, protonated imidazole-based ionic liquid-catalyzed cyclization was also selectively achieved with a nearly quantitative yield. Developed metal-free catalytic systems exhibited well adjustable and recyclable properties, avoiding the contamination of metal and halogen, reducing the neutralization after the reaction, and benefiting the separation between the catalyst and the product. New strategies were applied for performing the gram-scale reaction smoothly. The adjustable systems might occur through two different mechanisms involving propargylic or allenic carbocation and hydrogen bonding effects between the catalysts and the substrates.

Pharmacogenetics analysis of serotonin receptor gene variants and clinical response to risperidone in Han Chinese schizophrenic patients.

Assessments of the pharmacological profiles of antipsychotic agents have shown that the serotonin receptor family is often involved in their pharmacodynamics. Response to antipsychotic therapy is highly variable, yet prognostic biomarkers are lacking. The aim of the study was to investigate the association of 14 single nucleotide polymorphisms (SNPs) selected from HTR3C, HTR3D, HTR5A and HTR6 with risperidone response in 201 Han Chinese schizophrenia patients. The results showed that the HTR6 rs6699866 was significantly associated with risperidone response and predicted greater positive symptom reduction in risperidone-treated subjects (P = 0.04 and 0.004, respectively). The current study provides insight into the relationship between genetic polymorphisms in serotonin receptor family and risperidone therapeutic response in Han Chinese population. To clarify the role of these SNPs in clinical response to antipsychotic medication, and risperidone in particular, the study warrants further investigation in larger well-characterized samples.

Functional Characterization of Human CYP2C9 Allelic Variants in COS-7 Cells.

Variability in activity of CYP2C9, which is involved in the metabolism of approximately 15% of current therapeutic drugs, is an important contributor to interindividual differences in drug response. To evaluate the functional alternations of CYP2C9(*)2, CYP2C9(*)3, CYP2C9(*)8, CYP2C9(*)11 and CYP2C9(*)31, identified in our previous study in Chinese Han population, allelic variants as well as the wild-type CYP2C9 were transiently expressed in COS-7 cells. Kinetic parameters (Km, Vmax, and Clint) for S-warfarin 7-hydroxylation by these recombinant CYP2C9s were determined. Relative to CYP2C9.1, recombinant CYP2C9.3 and CYP2C9.11 exhibited significantly higher Km values, and all allelic variants showed significantly decreased Vmax and Clint values. Among all allelic variants, catalytic activity of CYP2C9.3 and CYP2C9.11 reduced the most (8.2% and 9.8% of Clint ratio, respectively; P < 0.001). These findings should be useful for predicting the phenotype profiles of CYP2C9 in Chinese Han population, comparing the functional results of these alleles accurately, and finally optimizing pharmacotherapy of drug treatment.

Association of dopamine receptor D1 (DRD1) polymorphisms with risperidone treatment response in Chinese schizophrenia patients.

Evidence suggests that dopamine receptor D1 (DRD1) may be involved in the pathophysiology of schizophrenia and the pharmacodynamics of antipsychotics. We conducted a comprehensive pharmacogenomics study to investigate the association of genetic polymorphisms in DRD1 with treatment response to risperidone. Two independent cohorts of Han Chinese schizophrenic patients (n = 185) from two different geographic areas treated with risperidone monotherapy for 4 weeks and four SNPs (rs5326, rs4867798, rs4532 and rs686) in the DRD1 gene were analyzed. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). The definition of risperidone response is based on a cut-off of 50% in terms of corrected percent change of PANSS score. The significant confounding effects of non-genetic factors were included as covariates for adjustment. No significant association of DRD1 polymorphisms with risperidone treatment response was found in either single marker or haplotype analysis in this study. The current results provide the first evidence that DRD1 polymorphisms may not influence the clinical efficacy of risperidone in Chinese schizophrenia patients.