Selective κ Opioid Antagonists nor-BNI, GNTI and JDTic Have Low Affinities for Non-Opioid Receptors and Transporters

Background: Nor-BNI, GNTI and JDTic induce selective κ opioid antagonism that is delayed and extremely prolonged, but some other effects are of rapid onset and brief duration. The transient effects of these compounds differ, suggesting that some of them may be mediated by other targets. Results: In binding assays, the three antagonists showed no detectable affinity (Ki≥10 µM) for most non-opioid receptors and transporters (26 of 43 tested). There was no non-opioid target for which all three compounds shared detectable affinity, or for which any two shared sub-micromolar affinity. All three compounds showed low nanomolar affinity for κ opioid receptors, with moderate selectivity over μ and δ (3 to 44-fold). Nor-BNI bound weakly to the α2C-adrenoceptor (Ki = 630 nM). GNTI enhanced calcium mobilization by noradrenaline at the α1A-adrenoceptor (EC50 = 41 nM), but did not activate the receptor, displace radioligands, or enhance PI hydrolysis. This suggests that it is a functionally-selective allosteric enhancer. GNTI was also a weak M1 receptor antagonist (KB = 3.7 µM). JDTic bound to the noradrenaline transporter (Ki = 54 nM), but only weakly inhibited transport (IC50 = 1.1 µM). JDTic also bound to the opioid-like receptor NOP (Ki = 12 nM), but gave little antagonism even at 30 µM. All three compounds exhibited rapid permeation and active efflux across Caco-2 cell monolayers. Conclusions: Across 43 non-opioid CNS targets, only GNTI exhibited a potent functional effect (allosteric enhancement of α1A-adrenoceptors). This may contribute to GNTI's severe transient effects. Plasma concentrations of nor-BNI and GNTI may be high enough to affect some peripheral non-opioid targets. Nonetheless, κ opioid antagonism persists for weeks or months after these transient effects dissipate. With an adequate pre-administration interval, our results therefore strengthen the evidence that nor-BNI, GNTI and JDTic are highly selective κ opioid antagonists

Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats

Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance

Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention behavior in rats

Background: Disruptions in perception and cognition are characteristic of psychiatric conditions such as schizophrenia. Studies of pharmacological agents that alter perception and cognition in humans might provide a better understanding of the brain substrates of these complex processes. One way to study these states in rodents is with tests that require attention and visual perception for correct performance. Methods: We examined the effects of two drugs that cause disruptions in perception and cognition in humans—the kappa-opioid receptor (KOR) agonist salvinorin A (salvA; 0.125–4.0 mg/kg) and the non-competitive NMDA receptor antagonist ketamine (0.63–20 mg/kg)—on behavior in rats using the 5-choice serial reaction time task (5CSRTT), a food-motivated test that quantifies attention. We also compared the binding profiles of salvA and ketamine at KORs and NMDA receptors. Results: SalvA and ketamine produced the same pattern of disruptive effects in the 5CSRTT, characterized by increases in signs often associated with reduced motivation (omission errors) and deficits in processing (elevated latencies to respond correctly). Sessions in which rats were fed before testing suggest that reduced motivation produces a subtly different pattern of behavior. Pretreatment with the KOR antagonist JDTic (10 mg/kg) blocked all salvA effects and some ketamine effects. Binding and function studies revealed that ketamine is a full agonist at KORs, although not as potent or selective as salvA. Conclusions: SalvA and ketamine have previously under-appreciated similarities in their behavioral effects and pharmacological profiles. By implication, KORs might be involved in some of the cognitive abnormalities observed in psychiatric disorders such as schizophrenia

Production of soluble, active acetyl serotonin methyl transferase in Leishmania tarentolae

International audienceN-acetyl serotonin methyl transferase (ASMT) is the last enzyme in the melatonin synthesis pathway. Evidence linking autism-related disorders with disorders of melatonin metabolism, and, more specifically, with mutations of the gene encoding ASMT, prompted us to investigate the properties and localization of this enzyme. As a first step, we undertook to overproduce the protein in a recombinant host. Early attempts to produce ASMT in recombinant Escherichia coli yielded only insoluble and heavily degraded material. However, recombinant ASMT (rASMT) could be produced in soluble, active form and purified in milligram amounts when the gene was cloned and expressed in Leishmania tarentolae

Turbine mode start-up simulation of a FSFC variable speed pump-turbine prototype ::Part I: 1D simulation

Variable speed hydroelectric units equipped with full size frequency converter (FSFC) offer high operational flexibility enabling fast operating point transitions which increase grid regulation capacities. The XFLEX HYDRO H2020 European research project aims to demonstrate flexibility of such technology at prototype scale. The Z'Mutt pumping station, part of the Grande Dixence hydroelectric scheme located in Switzerland, is one of the demonstrators focused on the FSFC technology with a new 5 MW reversible Francis pump-turbine which will be commissioned in 2021. This paper, divided in two parts, aims to simulate the turbine mode fast start-up sequence made possible with the use of a FSFC and to assess the unit damage by means of 1D and 3D CFD simulations. The part I of this paper presents the 1D hydraulic transient simulation results of start-up sequences of unit U5 considering both conventional fixed speed technology and variable speed technology. The time evolution of the unit's operating point is used as input data for 3D CFD simulations of part II, aiming to assess the impeller damage. Different control strategies to use the FSFC for turbine mode start-up sequence are analysed. Advantages and limits of each strategy are discussed, and recommendation is made for the Z'Mutt prototype demonstrator

Entre information et communication, les nouveaux espaces du document

Ce numéro s’inscrit dans la réflexion actuelle qui traverse les Sciences de l’Information et de la documentation autour de la notion de document, en rapport avec le développement des réseaux numériques. Le terme d’espaces est ici volontairement ambigu, car Études de Communication souhaite ouvrir un débat autour de cette notion à la fois quotidienne, technique et savante. Lorsqu’on parle d’Internet, les métaphores de l’espace se multiplient : outre les images rebattues liées à la navigation, au parcours, à l’exploration, il est question de cartes conceptuelles, de géographie des sites, mais aussi de profondeur, de dimension cachée... autant de termes qui ramènent à l’indexation et aux procédures de guidage dans l’univers des signes. Il semble quasi impossible d’élaborer une conception d’Internet sans recourir à des images mentales à caractère spatial. Les espaces réels, symboliques et imaginaires concernent à la fois la dimension cognitive du document, sa dimension technique et sa dimension sociale. En ce sens, étudier les espaces du document et/ou ses métamorphoses conduit à de multiples questionnements. Interrogations que se propose d’explorer le trentième numéro d’Études de Communication. This issue is part of the current reflection running through the information and documentation sciences concerning the notion of the document in relation to the development of digital networks. Use of the term “spaces” is voluntarily ambiguous because Études de Communications wants to open the debate on this idea that is at once routine, technical, and scholarly. When we speak about the Internet, metaphors of space are multiple: other than images borrowed from navigation, itineraries, or exploration, there is the question of conceptual maps, site geography, but also depth, hidden dimensions . . . terms that refer to the indexation of piloting procedures in the universe of signs. It seems almost impossible to discuss the idea of the Internet without recourse to mental images related to space. Real, symbolic, and imaginary spaces concern both the cognitive dimension of the document, and its technical and social dimensions. In this sense, studying the spaces of the document and/or its transformations leads to multiple questions which the thirtieth issue of Études de Communications intends to explore

8-epi-Salvinorin B: crystal structure and affinity at the κ opioid receptor

There have been many reports of epimerization of salvinorins at C-8 under basic conditions, but little evidence has been presented to establish the structure of these compounds. We report here the first crystal structure of an 8-epi-salvinorin or derivative: the title compound, 2b. The lactone adopts a boat conformation with the furan equatorial. Several lines of evidence suggest that epimerization proceeds via enolization of the lactone rather than a previously proposed indirect mechanism. Consistent with the general trend in related compounds, the title compound showed lower affinity at the kappa opioid receptor than the natural epimer salvinorin B (2a). The related 8-epi-acid 4b showed no affinity