DARK Classics in Chemical Neuroscience: Aminorex Analogues

Aminorex (5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) and 4-methylaminorex (4-methyl-5-phenyl-4,5-dihydro-1,3-oxazol-2-amine) are psychostimulants that have long been listed in Schedules IV and I of the UN Convention on Psychotropic Substances of 1971. However, a range of psychoactive analogs exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogs encompass failed pharmaceuticals that reemerged as drugs of abuse, and newly synthesized substances that were solely designed for recreational use by clandestine chemists. NPS, sometimes also referred to as “designer drugs” in alignment with a phenomenon arising in the early 1980s, serve as alternatives to controlled drugs. Aminorex and its derivatives interact with monoaminergic neurotransmission by interfering with the function of monoamine transporters. Hence, these compounds share pharmacological and neurochemical similarities with amphetamines and cocaine. The consumption of aminorex, 4-methylaminorex and 4,4’-dimethylaminorex (4-methyl-5-(4-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine) has been associated with adverse events including death, bestowing an inglorious fame on aminorex-derived drugs. In this review, a historical background is presented, as well as an account of the pharmacodynamic and pharmacokinetic properties of aminorex and various analogs. Light is shed on their misuse as drug adulterants of well-established drugs on the market. This review not only provides a detailed overview of an abused substance-class, but also emphasizes the darkest aspect of the NPS market, i.e. deleterious side effects that arise from the ingestion of certain NPS, as knowledge of the pharmacology, the potency or the identity of the active ingredients remains obscure to NPS users

A systematic review of the evidence on decoupling of GDP, resource use and GHG emissions, part II: synthesizing the insights

Strategies toward ambitious climate targets usually rely on the concept of "decoupling"; that is, they aim at promoting economic growth while reducing the use of natural resources and GHG emissions. GDP growth coinciding with absolute reductions in emissions or resource use is denoted as "absolute decoupling", as opposed to "relative decoupling", where resource use or emissions increase less so than does GDP. Based on the bibliometric mapping in part I (Wiedenhofer et al., this issue), we synthesize the evidence emerging from the selected 835 peer-reviewed articles. We evaluate empirical studies of decoupling related to final/useful energy, exergy, use of material resources, as well as CO2 and total GHG emissions. We find that relative decoupling is frequent for material use as well as GHG and CO2 emissions but not for useful exergy, a quality-based measure of energy use. Primary energy can be decoupled from GDP largely to the extent to which the conversion of primary energy to useful exergy is improved. Examples of absolute long-term decoupling are rare, but recently some industrialized countries have decoupled GDP from both production- and, weaklier, consumption-based CO2 emissions. We analyze policies or strategies in the decoupling literature by classifying them into three groups: (1) Green growth, if sufficient reductions of resource use or emissions were deemed possible without altering the growth trajectory. (2) Degrowth, if reductions of resource use or emissions were given priority over GDP growth. (3) Others, e.g. if the role of energy for GDP growth was analyzed without reference to climate change mitigation. We conclude that large rapid absolute reductions of resource use and GHG emissions cannot be achieved through observed decoupling rates, hence decoupling needs to be complemented by sufficiency-oriented strategies and strict enforcement of absolute reduction targets. More research is needed on interdependencies between wellbeing, resources and emissions

A systematic review of the evidence on decoupling of GDP, resource use and GHG emissions, part I: bibliometric and conceptual mapping

As long as economic growth is a major political goal, decoupling growth from resource use and emissions is a prerequisite for a sustainable net-zero emissions future. However, empirical evidence for absolute decoupling, i.e., decreasing resource use and emissions at the required scale despite continued economic growth, is scarce and scattered across different research streams. In this two-part systematic review, we assess how and to what extent decoupling has been observed and what can be learnt for addressing the sustainability and climate crisis. Based on a transparent approach, we systematically identify and screen more than 11,500 scientific papers, eventually analyzing full texts of 835 empirical studies on the relationship between economic growth (GDP), resource use (materials and energy) and greenhouse gas emissions. Part I of the review examines how decoupling has been investigated across three research streams: energy, materials and energy, and emissions. Part II synthesizes the empirical evidence and policy implications (Haberl et al. part II, in review). In part I, we examine the topical, temporal and geographical scopes, methods of analysis, institutional networks and prevalent conceptual angles. We find that in this rapidly growing literature, the vast majority of studies – decomposition, 'causality' and Environmental Kuznets Curve analysis – approach the topic from a statistical-econometric point of view, while hardly acknowledging thermodynamic principles on the role of energy and materials for socio-economic activities. A potentially fundamental incompatibility between economic growth and systemic societal changes to address the climate crisis is rarely considered. We conclude that the existing wealth of empirical evidence merits braver conceptual advances than we have seen thus far. Future work should focus on comprehensive multi-indicator long-term analyses, conceptually grounded on the fundamental biophysical basis of socio-economic activities, incorporating the role of global supply chains as well as the wider societal role and preconditions of economic growth

Fluorinated phenmetrazine “legal highs” act as substrates for high-affinity monoamine transporters of the SLC6 family

A variety of new psychoactive substances (NPS) are appearing in recreational drug markets worldwide. NPS are compounds that target various receptors and transporters in the central nervous system to achieve their psychoactive effects. Chemical modifications of existing drugs can generate NPS that are not controlled by current legislation, thereby providing legal alternatives to controlled substances such as cocaine or amphetamine. Recently, 3-fluorophenmetrazine (3-FPM), a derivative of the anorectic compound phenmetrazine, appeared on the recreational drug market and adverse clinical effects of the drug have been reported. Phenmetrazine is known to elevate extracellular monoamine concentrations by an amphetamine-like mechanism. Here we tested 3-FPM and its positional isomers, 2-FPM and 4-FPM, for their abilities to interact with plasma membrane monoamine transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). We found that 2-, 3- and 4-FPM inhibit uptake mediated by DAT and NET in HEK293 cells with potencies comparable to cocaine (IC50 values 50 µM). Experiments directed at identifying transporter-mediated reverse transport revealed that FPM isomers induce efflux via DAT, NET and SERT in HEK293 cells, and this effect is augmented by the Na+/H+ ionophore monensin. Each FPM evoked concentration-dependent release of monoamines from rat brain synaptosomes. Hence, this study reports for the first time the mode of action for 2-, 3- and 4-FPM and identifies these NPS as monoamine releasers with marked potency at catecholamine transporters implicated in abuse and addiction

E-cadherin and Cytokeratin Subtype Profiling in Effusion Cytology

Diagnostic utility of E-cadherin (E-CD) and cytokeratin (CK) subtype profiling in effusion cytology was investigated, employing immunocytochemistry on cellblock sections available from 211 metastatic carcinomas (MC), 6 mesotheliomas and 73 reactive mesothelial hyperplasias (MH). E-CD and monoclonal carcinoembryonic anti-gen (mCEA) stained 85% (120/141) and 65% (138/211) of MC, respectively. E-CD staining of MC was frequently heterogeneous (76/120) and absent in all anaplastic carcinomas (0/2). E-CD stained none (0/57) of MH while mCEA and epithelial membrane antigen (EMA) stained 12% (9/73) and 32% (16/32) of MH, respectively. Of 6 mesotheliomas, E-CD focally stained in 2 while mCEA stained none and EMA stained all. CK20 and CK17 stained none of MH or mesotheliomas. CK20 stained 15% of MC and CK 17 stained 22% of MC. CK5/6 and high molecular weight CK stained all mesotheliomas, 56% and 88% of MH, 26% and 39% of MC, respectively. MC showed predominant CK7+/20- expression, with the exceptions of MC from mucinous type of colon/rectum and ovary showing predominant CK20 positive. E-CD may be a useful positive marker for MC in effusion cytology, although it may focally stain in some mesotheliomas. Any positive staining for CK20 of MC suggests MC from the gastrointestinal tract or ovary among others

Star forming dwarf galaxies

Star forming dwarf galaxies (SFDGs) have a high gas content and low metallicities, reminiscent of the basic entities in hierarchical galaxy formation scenarios. In the young universe they probably also played a major role in the cosmic reionization. Their abundant presence in the local volume and their youthful character make them ideal objects for detailed studies of the initial stellar mass function (IMF), fundamental star formation processes and its feedback to the interstellar medium. Occasionally we witness SFDGs involved in extreme starbursts, giving rise to strongly elevated production of super star clusters and global superwinds, mechanisms yet to be explored in more detail. SFDGs is the initial state of all dwarf galaxies and the relation to the environment provides us with a key to how different types of dwarf galaxies are emerging. In this review we will put the emphasis on the exotic starburst phase, as it seems less important for present day galaxy evolution but perhaps fundamental in the initial phase of galaxy formation.Comment: To appear in JENAM Symposium "Dwarf Galaxies: Keys to Galaxy Formation and Evolution", P. Papaderos, G. Hensler, S. Recchi (eds.). Lisbon, September 2010, Springer Verlag, in pres

Recent research on changes in genomic regulation and protein expression in intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is a devastating form of stroke that accounts for roughly 10% of all strokes and the effects on those that survive are often debilitating. To date, no suitable therapy exists. Recent work has examined alterations in gene and protein expression after ICH. The focus of this review is to outline the current knowledge of changes in genetic and protein expression after ICH and how those changes may affect the course of brain injury. Both animal and human data are reviewed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73607/1/j.1747-4949.2007.00160.x.pd

The psychostimulant (±)-cis-4,4'-dimethylaminorex (4,4'-DMAR) interacts with human plasmalemmal and vesicular monoamine transporters

(±)-cis-4,4'-Dimethylaminorex (4,4'-DMAR) is a new psychoactive substance (NPS) that has been associated with 31 fatalities and other adverse events in Europe between June 2013 and February 2014. However, the pharmacology of 4,4'-DMAR remains largely unexplored. We used in vitro uptake inhibition and transporter release assays to determine the effects of 4,4'-DMAR on human high-affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). In addition, we assessed its binding affinities to monoamine receptors and transporters. Furthermore, we investigated the interaction of 4,4'-DMAR with the vesicular monoamine transporter 2 (VMAT2) in rat phaeochromocytoma (PC12) cells and synaptic vesicles prepared from human striatum. 4,4'-DMAR inhibited uptake mediated by human DAT, NET or SERT, respectively in the low micromolar range (IC50 values < 2 µM). Release assays identified 4,4'-DMAR as a substrate type releaser, capable of inducing transporter-mediated reverse transport via DAT, NET and SERT. Furthermore, 4,4'-DMAR inhibited both the rat and human isoforms of VMAT2 at a potency similar to 3,4-methylenedioxymethylamphetamine (MDMA).This study identified 4,4'-DMAR as a potent non-selective monoamine releasing agent. In contrast to the known effects of aminorex and 4-methylaminorex, 4,4'-DMAR exerts profound effects on human SERT. The latter finding is consistent with the idea that fatalities associated with its abuse may be linked to monoaminergic toxicity including serotonin syndrome. The activity at VMAT2 suggests that chronic abuse of 4,4'-DMAR may result in long-term neurotoxicity