Anxiolytic-like effects of 8-acetylene imidazobenzodiazepines in a rhesus monkey conflict procedure

Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABAA receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABAA receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH3 and SH-053-2'F-R-CH3 at GABAA receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABAA receptors containing α1 subunits and varying degrees of efficacy and affinity at GABAA receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABAA receptors containing α1 and α5 subunits. In contrast, SH-053-2’F-S-CH3 and SH-053-2’F-R-CH3 produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABAA receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABAA receptor positive modulators are dependent on their relative efficacy and affinity at different GABAA receptor subtypes

Operation experience with a novel highly efficient micro-scale CHP system based on fuel-flexible gasification and a SOFC

An efficient and fuel flexible micro-scale biomass CHP technology based on the combination of a small-scale updraft gasifier with a SOFC system is developed within the project FlexiFuel-SOFC. High load flexibility and a maximum of full load operating hours of the CHP system is achieved by operating the CHP part of the plant with a side stream (product gas extracted from the gasifier) of a heat controlled system (gas burner and boiler as well as heat recovery). A gas cleaning unit (GCU) for the treatment of the side stream according to the requirements for the operation of the SOFC regarding contaminant (H2S, HCl) and TSP removal as well as tar content reduction was designed, constructed and successfully evaluated. A considerable reduction of the gravimetric tar content down to a suitable tar content for the operation of the SOFC stack module is achieved by gasifier internal tar reformation and a further reformation step in the tar reformer of the GCU. Comprehensive tests have been successfully performed with a broad spectrum of solid biomass fuels at a testing plant at BIOS in Graz. Promising test run results showing a basic proof of concept for the new technology could be gained

Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface

Zolpidem is not a typical GABA(A) receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary α1β3 GABA(A) receptors in either the 3α1:2β3 or 2α1:3β3 subunit stoichiometry, which differ by the existence of either an α1-α1 interface, or a β3-β3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn(2+). At the 3α1:2β3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2α1:3β3 receptor, indicating that the binding site for zolpidem is at the α1-α1 interface, a site mimicking the classical α1-γ2 benzodiazepine site. Activating α1β3 (3α1:2β3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target

Diazepam-bound structure of the GABAA receptor identifies novel ligands for the benzodiazepine binding site

Benzodiazepines exert their anxiolytic, anticonvulsant, muscle-relaxant and sedative-hypnotic properties by allosterically enhancing the action of GABA at GAB