james cook

In non-small cell lung cancer (NSCLC) treatment, targeted therapies benefit only a subset of NSCLC, while radiotherapy responses are not durable and toxicity limits therapy. We find that a GABA(A) receptor activator, AM-101, impairs viability and clonogenicity of NSCLC primary and brain metastatic cells. Employing an ex vivo chip, AM-101 is as efficacious as the chemotherapeutic docetaxel, which is used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a survival benefit to mice bearing NSCLC intracranial tumors. GABA(A) receptor activation stimulates a selective-autophagic response via multimerization of GABA(A) Receptor-Associated Protein (GABARAP), stabilization of mitochondrial receptor Nix, and utilization of ubiquitin-binding protein p62. A targeted-peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis triggering autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.

Recent studies suggest that amongst the GABAA receptor subtype heterogeneity, α2/α3 subunits of GABAA receptors mediate pain processing. Therefore, α2/α3-subtype selective GABAA receptor positive allosteric modulators (PAMs) may be candidate analgesics. Antinociceptive effects of α2/α3-subtype selective GABAA receptor PAMs have been reported, but the behavioral effects of these compounds have not been systematically evaluated. This study examined the behavioral effects of two α2/α3 subtype-selective GABAA receptor PAMs, KRM-II-81 and NS16085, in male rats. The antinociceptive effects of KRM-II-81 and NS16085 were examined using rat models of inflammatory (complete Freund9s adjuvant) and neuropathic pain (chronic constriction injury). The effect of KRM-II-81 on affective pain was measured using the place escape/avoidance paradigm (PEAP). Rate-response of food-maintained operant …

Provided herein are alpha5-containing GABA A receptor agonists and pharmaceutical compositions and methods of treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders using them.

The low aqueous and oil solubility of the novelpyrazoloquinolinone ligand (CW-02-79) with significantbinding affinity for sigma-2 receptors in the brain hindersthe development of conventional parenteral formulationsand thus a comprehensive evaluation of its efficacy andsafety. ...

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970's. Meclonazepam was not brought to market because of dose-limiting sedative side effects. However, the human target of meclonazepam that causes sedation (GABAARs) are not orthologous to the parasite targets that cause worm death. Therefore, we were interested in whether the structure of meclonazepam could be modified to produce antiparasitic benzodiazepines that do not cause host sedation. We synthesized 18 meclonazepam derivatives with modifications at different positions on the benzodiazepine ring system and tested them for in vitro antiparasitic activity. This identified five compounds that progressed to in vivo screening in a murine model, two of which cured parasite infections with comparable potency to meclonazepam. When these two compounds were administered to mice that were run on the rotarod test, both were less sedating than meclonazepam. These findings demonstrate the proof of concept that meclonazepam analogs can be designed with an improved therapeutic index, and point to the C3 position of the benzodiazepine ring system as a logical site for further structure-activity exploration to further optimize this chemical series.

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the α5, but not α1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that α1GABAARs are primarily located in the synapse, whereas α5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds α5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of α5GABAARs (α5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting α5GABAARs from the extrasynaptic space to the …

Bisphenol A (BPA) and its chlorinated derivatives (Clx-BPA) are environmental pollutants exhibiting endocrine-disrupting (ED) properties suspected to be involved in the pathogenesis of hormone-dependent cancers, such as breast and prostate cancers. Due to their lipophilic properties, they may accumulate in adipose tissue which could therefore be a suitable matrix to assess long-term exposure to these compounds and relationships with the tumorigenesis of these cancers. An LC-MS/MS assay for the determination of BPA and Clx-BPA in adipose tissue samples was developed and fully validated according to current bioanalytical validation guidelines. Ionization was achieved using an electrospray source operating in the negative mode and quantification of target analytes was obtained in the multiple reaction monitoring mode. Both standard and quality control (QC) samples were prepared in blank adipose …

BackgroundReduced GABA/somatostatin (SST) signaling is reported in psychiatric, stress-related and neurodegenerative disorders. Cortical SST+ interneurons inhibit the dendrites of excitatory neurons, largely through α5-containing GABAA receptors (α5-GABAAR). We showed that an α5-positive allosteric modulator (α5-PAM) alleviates working memory deficits and reverses neuronal atrophy in old mice. We then started to investigate the behavioral and neurotrophic effects of this α5-PAM in animal models of aging, chronic stress, β-amyloid load, and tauopathy.MethodsFour studies are presented (∼ 12 mice/group, 50% female): 1) Young C57BL6 subjected to chronic stress. 2) 22-month-old C57BL6 developing an age-related cognitive decline. 3) 5xFAD transgenic mice with progressive amyloid load. 4) PS19 transgenic mice developing tauopathy. Efficacy of 4 weeks of GL-II-73 (30mg/kg, po) at rescuing …