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SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its analogues 11a-c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus COX-1 enzyme.

The QuantiFERON-TB gold in-tube assay (QFT) (Cellestis/ Qiagen, Australia) is increasingly being utilized in the diagnosis of latent tuberculosis (TB) infection (LTBI). However, the use of interferon (gamma interferon [IFN-␥]) release assays (IGRAs) for other indications is debated. Can IGRAs be used to monitor the response to treatment of active TB? Some reports have suggested that IFN-␥ responses decline with decreasing antigenic load during treatment (1-3). Most of these studies have included small numbers of patients in countries where TB is endemic, and few have tried to correlate changes in IFN-␥ responses with established, albeit imperfect, markers of treatment response in pulmonary TB (i.e., smear and culture conversion to negativity) (2, 4).We evaluated 172 patients with active TB at different health centers in Montreal, Canada. The patients received treatment according to the recommendations of the Canadian Tuberculosis Standards (5). Directly observed therapy (DOT) was left to the discretion of the treating physician. QFT was done at the time of diagnosis, after 2 months, and at the end of treatment (between 6 to 9 months for most patients). The study was approved by the institutional review board of McGill University. We performed all QFT testing per the manufacturer's instructions in one laboratory. We evaluated QFT reversion and conversion rates using the manufacturers' definition (i.e., change from negative to positive and vice versa with a cutoff IFN-␥ of Ն0.35 IU/ml). We assessed whether QFT reversion or a decline in quantitative IFN-␥ results after 2 months of treatment was associated with smear or culture conversion to negativity after 2 months of treatment.We performed all analyses with Stata, version 12 (Stata Corp., TX). We excluded 2 participants with indeterminate results and 21 participants without QFT results pretreatment from further analysis. Because the distribution of IFN-␥ values in the individual groups was not normal, we used nonparametric tests (KruskalWallis test) to assess the difference between median IFN-␥ levels between different groups of patients (based on smear and culture status). Differences in the quantitative IFN-␥ results at baseline, after 2 months of treatment, and at the end of treatment were compared using a Wilcoxon signed rank test to account for paired data. Logistic regression was used to assess the association of QFT results as a qualitative variable (positive/negative) with culture or smear results after 2 months of treatment after adjustment for other covariates.The mean age of the patients was 37 years (range, 3 to 82 years), and 59% of patients were male. Most patients (93%) were foreignborn and came from countries with a high prevalence of TB. The age at immigration on average was 22 years. Almost 15% of all cases had some form of immunosuppression (i.e., HIV, therapy with steroids, malignancy, or diabetes). Of the active TB cases, 128 (86%) were pulmonary, and 20 (14%) were extrapulmonary (predominantly lymph node disease). Pulmonary disease was cultu...

Background and purpose: To further assess the clinical potential of the blockade of metabotropic glutamate receptors (mGluR1) for the treatment of pain. Experimental approach: We characterized the effects of A-841720, a novel, potent and non-competitive mGluR1 antagonist in models of pain and of motor and cognitive function. Key results: At recombinant human and native rat mGluR1 receptors, A-841720 inhibited agonist-induced calcium mobilization, with IC 50 values of 10.773.9 and 1.070.2 nM, respectively, while showing selectivity over other mGluR receptors, in addition to other neurotransmitter receptors, ion channels, and transporters. Intraperitoneal injection of A-841720 potently reduced complete Freund's adjuvant-induced inflammatory pain (ED 50 ¼ 23 mmol kg À1 ) and monoiodoacetate-induced joint pain (ED 50 ¼ 43 mmol kg À1 ). A-841720 also decreased mechanical allodynia observed in both the sciatic nerve chronic constriction injury and L5-L6 spinal nerve ligation (SNL) models of neuropathic pain (ED 50 ¼ 28 and 27 mmol kg À1 , respectively). Electrophysiological studies demonstrated that systemic administration of A-841720 in SNL animals significantly reduced evoked firing in spinal wide dynamic range neurons. Significant motor side effects were observed at analgesic doses and A-841720 also impaired cognitive function in the Y-maze and the Water Maze tests. Conclusions and implications. The analgesic effects of a selective mGluR1 receptor antagonist are associated with motor and cognitive side effects. The lack of separation between efficacy and side effects in pre-clinical models indicates that mGluR1 antagonism may not provide an adequate therapeutic window for the development of such antagonists as novel analgesic agents in humans.