Publications by authors named "Harald H Sitte"

145 Publications

Effects of Hydroxylated Mephedrone Metabolites on Monoamine Transporter Activity .

Front Pharmacol 2021 9;12:654061. Epub 2021 Apr 9.

Institute of Applied Synthetic Chemistry, TU Wien, Vienna, Austria.

Mephedrone is a largely abused psychostimulant. It elicits the release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Stereoselective metabolic reactions are involved in the inactivation and the elimination of its chemical structure. However, during these processes, several structures are generated and some of them have been reported to be still pharmacologically active. In this study 1) we have newly synthetized several putative mephedrone metabolites, 2) compared their activity at monoamine transporters, 3) generated quantitative structure activity relationships, and 4) exploited the chemical structure of the putative metabolites to screen a urine sample from a drug user and dissect mephedrone metabolism. We have found that most of the tested metabolites are weak inhibitors of monoamine transporters and that all of them are more potent at DAT and NET in comparison to SERT. The only exception is represented by the COOH-metabolite which shows no pharmacological activity at all three monoamine transporters. The enantioselectivity of mephedrone and its metabolites is present mainly at SERT, with only minor effects at DAT and NET being introduced when the β-keto group is reduced to an OH-group. Importantly, while at DAT the putative metabolites did not show changes in inhibitory potencies, but rather changes in their substrate/blocker profile, at SERT they showed mainly changes in inhibitory potencies. Molecular modeling suggests that the hydrophobic nature of a specific SERT subpocket may be involved in such loss of affinity. Finally, the assessment of the putative metabolites in one urine sample of mephedrone user displayed two previously uncharacterized metabolites, 4-COOH-nor-mephedrone (4-COOH-MC) and dihydro-4- nor-mephedrone (dihydro-4-MC). These results confirm and expand previous studies highlighting the importance of the stereochemistry in the pharmacodynamics of phase-1 metabolites of mephedrone, established their structure-activity relationships at DAT, NET and SERT and pave the way for a systematic dissection of mephedrone metabolic routes. Given the number of structures found having residual and modified pharmacological profiles, these findings may help in understanding the complex subjective effects of administered mephedrone. Moreover, the dissection of mephedrone metabolic routes may help in developing new therapies for treating psychostimulants acute intoxications.
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http://dx.doi.org/10.3389/fphar.2021.654061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063026PMC
April 2021

α-PPP and its derivatives are selective partial releasers at the human norepinephrine transporter: A pharmacological characterization of interactions between pyrrolidinopropiophenones and uptake1 and uptake2 monoamine transporters.

Neuropharmacology 2021 Apr 20;190:108570. Epub 2021 Apr 20.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Währingerstraße 13A, 1090, Vienna, Austria; AddRess Centre for Addiction Research and Science, Medical University of Vienna, Währingerstraße 13A, 1090, Vienna, Austria. Electronic address:

While classical cathinones, such as methcathinone, have been shown to be monoamine releasing agents at human monoamine transporters, the subgroup of α-pyrrolidinophenones has thus far solely been characterized as monoamine transporter reuptake inhibitors. Herein, we report data from previously undescribed α-pyrrolidinopropiophenone (α-PPP) derivatives and compare them with the pharmacologically well-researched α-PVP (α-pyrrolidinovalerophenone). Radiotracer-based in vitro uptake inhibition assays in HEK293 cells show that the investigated α-PPP derivatives inhibit the human high-affinity transporters of dopamine (hDAT) and norepinephrine (hNET) in the low micromolar range, with α-PVP being ten times more potent. Similar to α-PVP, no relevant pharmacological activity was found at the human serotonin transporter (hSERT). Unexpectedly, radiotracer-based in vitro release assays reveal α-PPP, MDPPP and 3Br-PPP, but not α-PVP, to be partial releasing agents at hNET (EC values in the low micromolar range). Furthermore, uptake inhibition assays at low-affinity monoamine transporters, i.e., the human organic cation transporters (hOCT) 1-3 and human plasma membrane monoamine transporter (hPMAT), bring to light that all compounds inhibit hOCT1 and 2 (IC values in the low micromolar range) while less potently interacting with hPMAT and hOCT3. In conclusion, this study describes (i) three new hybrid compounds that efficaciously block hDAT while being partial releasers at hNET, and (ii) highlights the interactions of α-PPP-derivatives with low-affinity monoamine transporters, giving impetus to further studies investigating the interaction of drugs of abuse with OCT1-3 and PMAT.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108570DOI Listing
April 2021

Targeting interleukin-6 to treat neuromyelitis optica spectrum disorders: Implications from immunology, the FcRn pathway and clinical experience.

Drug Discov Today 2021 Mar 27. Epub 2021 Mar 27.

Department of Neurology, Medical University of Vienna, Vienna, Austria; Neuroimmunological Section, Department of Neurology, University of Rostock, Rostock, Germany. Electronic address:

Neuromyelitis optica spectrum disorder (NMOSD) is a rare disease of the central nervous system (CNS) that is associated with poor outcomes for patients. Until recently, when complement inhibitors were approved, there was no approved therapy. Most recently, clinical trials of interleukin-6 (IL-6) blockade showed a therapeutic benefit for NMOSD. In this review, we introduce the immunological basis of IL-6 blockade in NMOSD and summarize current knowledge about the clinical use of the IL-6 receptor inhibitors tocilizumab and satralizumab. The aim of extending the half-life of monoclonal antibodies (mAbs) has been actualized by successful clinical translation for Satralizumab, achieved via the neonatal Fc receptor (FcRn) pathway. The basic principles of FcRn are highlighted in this review together with the potential therapeutic benefits of this emerging technology.
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http://dx.doi.org/10.1016/j.drudis.2021.03.018DOI Listing
March 2021

Ga-Labelled Tropane Analogues for the Visualization of the Dopaminergic System.

ChemMedChem 2021 Mar 10;16(5):804-808. Epub 2020 Dec 10.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.

The development of radiometal-labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood-brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of Ga-labelled phenyltropanes showing that, through a simple hydrocarbon-linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequate lipophilicity. One of the candidates, [ Ga]Ga-HBED-hexadiyne-tropane, showed an IC value of 66 nM, together with a log D of 0.96. A μPET study in a hemi-parkinsonian rat model showed a fast wash-out of the tracer, and no specific uptake in the brain, thus implying an inability to penetrate the BBB.
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http://dx.doi.org/10.1002/cmdc.202000820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984292PMC
March 2021

Saturation transfer difference NMR on the integral trimeric membrane transport protein GltPh determines cooperative substrate binding.

Sci Rep 2020 10 5;10(1):16483. Epub 2020 Oct 5.

Henry Wellcome Unit for Biological EPR, School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK.

Saturation-transfer difference (STD) NMR spectroscopy is a fast and versatile method which can be applied for drug-screening purposes, allowing the determination of essential ligand binding affinities (K). Although widely employed to study soluble proteins, its use remains negligible for membrane proteins. Here the use of STD NMR for K determination is demonstrated for two competing substrates with very different binding affinities (low nanomolar to millimolar) for an integral membrane transport protein in both detergent-solubilised micelles and reconstituted proteoliposomes. GltPh, a homotrimeric aspartate transporter from Pyrococcus horikoshii, is an archaeal homolog of mammalian membrane transport proteins-known as excitatory amino acid transporters (EAATs). They are found within the central nervous system and are responsible for fast uptake of the neurotransmitter glutamate, essential for neuronal function. Differences in both K's and cooperativity are observed between detergent micelles and proteoliposomes, the physiological implications of which are discussed.
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http://dx.doi.org/10.1038/s41598-020-73443-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536232PMC
October 2020

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters.

Biomolecules 2020 08 20;10(9). Epub 2020 Aug 20.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Währinger Strasse 42, A-1090 Vienna, Austria.

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([HL]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL)Cl]Cl (-) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: > > > > >[HL]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
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http://dx.doi.org/10.3390/biom10091213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565988PMC
August 2020

SLC6 transporter oligomerization.

J Neurochem 2020 Aug 7. Epub 2020 Aug 7.

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

Transporters of the solute carrier 6 (SLC6) family mediate the reuptake of neurotransmitters such as dopamine, norepinephrine, serotonin, GABA, and glycine. SLC6 family members are 12 transmembrane helix-spanning proteins that operate using the transmembrane sodium gradient for transport. These transporters assume various quaternary arrangements ranging from monomers to complex stoichiometries with multiple subunits. Dopamine and serotonin transporter oligomerization has been implicated in trafficking of newly formed proteins from the endoplasmic reticulum to the plasma membrane with a pre-fixed assembly. Once at the plasma membrane, oligomers are kept fixed in their quaternary assembly by interaction with phosphoinositides. While it remains unclear how oligomer formation precisely affects physiological transporter function, it has been shown that oligomerization supports the activity of release-type psychostimulants. Most recently, single molecule microscopy experiments unveiled that the stoichiometry differs between individual members of the SLC6 family. The present overview summarizes our understanding of the influence of plasma membrane constituents on transporter oligomerization, describes the known interfaces between protomers and discusses open questions.
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http://dx.doi.org/10.1111/jnc.15145DOI Listing
August 2020

Allosterically Linked Binding Sites in Serotonin Transporter Revealed by Single Molecule Force Spectroscopy.

Front Mol Biosci 2020 3;7:99. Epub 2020 Jun 3.

Institute of Biophysics, Johannes Kepler University Linz, Linz, Austria.

Crystal structures and experiments relying on the tools of molecular pharmacology reported conflicting results on ligand binding sites in neurotransmitter/sodium symporters (NSS). We explored the number and functionality of ligand binding sites of NSS in a physiological setting by designing novel tools for atomic force microscopy (AFM). These allow for directly measuring the interaction forces between the serotonin transporter (SERT) and the antidepressant S-citalopram (S-CIT) on the single molecule level: the AFM cantilever tips were functionalized with S-CIT via a flexible polyethylene glycol (PEG) linker. The tip chemistry was validated by specific force measurements and recognition imaging on CHO cells. Two distinct populations of characteristic binding strengths of S-CIT binding to SERT were revealed in Na-containing buffer. In contrast, in Li-containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT-G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT. The dissociation rate constant of both binding sites was extracted by varying the dynamics of the force-probing experiments. Competition experiments revealed that the two sites are allosterically coupled and exert reciprocal modulation.
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http://dx.doi.org/10.3389/fmolb.2020.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325972PMC
June 2020

Cell-Based Radiotracer Binding and Uptake Inhibition Assays: A Comparison of Methods to Assess the Potency of Drugs That Target Monoamine Transporters.

Front Pharmacol 2020 19;11:673. Epub 2020 May 19.

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

High-affinity monoamine transporters are targets for prescribed medications and stimulant drugs of abuse. Therefore, assessing monoamine transporter activity for candidate medications and newly-emerging drugs of abuse provides essential information for industry, academia, and public health. Radiotracer binding and uptake inhibition are the gold standard assays for determining drug-transporter interaction profiles. The combined results from such assays yield a unique biochemical fingerprint for each compound. Over time, different assay methods have been developed to assess transporter activity, and the comparability of data across various assay platforms remains largely unclear. Here, we compare the effects of six well-established stimulants in two different cell-based uptake inhibition assays, one method using adherent cells and the other using suspended cells. Furthermore, we compare the data from transfected cell lines derived from different laboratories and data reported from rat synaptosomes. For transporter inhibitors, IC values obtained by the two experimental methods were comparable, but using different transfected cell lines yielded disparate results. For transporter substrates, differences between the two cell lines were less pronounced but the drugs displayed different inhibition potencies when evaluated by the two methods. Our study illustrates the inherent limitations when comparing transporter inhibition data from different laboratories and stresses the importance of including appropriate control experiments with reference compounds when investigating new drugs of interest.
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http://dx.doi.org/10.3389/fphar.2020.00673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248194PMC
May 2020

Allosteric Modulation of Neurotransmitter Transporters as a Therapeutic Strategy.

Trends Pharmacol Sci 2020 07 26;41(7):446-463. Epub 2020 May 26.

Centre for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria; AddRess, Centre for Addiction Research and Science, Medical University of Vienna, Vienna, Austria. Electronic address:

Neurotransmitter transporters (NTTs) are involved in the fine-tuning of brain neurotransmitter homeostasis. As such, they are implicated in a plethora of complex behaviors, including reward, movement, and cognition. During recent decades, compounds that modulate NTT functions have been developed. Some of them are in clinical use for the management of different neuropsychiatric conditions. The majority of these compounds have been found to selectively interact with the orthosteric site of NTTs. Recently, diverse allosteric sites have been described in a number of NTTs, modulating their function. A more complex NTT pharmacology may be useful in the development of novel therapeutics. Here, we summarize current knowledge on such modulatory allosteric sites, with specific focus on their pharmacological and therapeutic potential.
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http://dx.doi.org/10.1016/j.tips.2020.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610661PMC
July 2020

Esoterism in medicine.

Wien Klin Wochenschr 2020 05;132(9-10):223

Medical University Vienna, Spitalgasse 23, Vienna, 1090, Austria.

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http://dx.doi.org/10.1007/s00508-019-01571-2DOI Listing
May 2020

Syntheses and analytical characterizations of novel (2-aminopropyl)benzo[b]thiophene (APBT) based stimulants.

Drug Test Anal 2020 Aug 10;12(8):1109-1125. Epub 2020 Jun 10.

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

Two groups of amphetamine-like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzo[b]thiophene structure (resulting in (2-aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT-type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.
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http://dx.doi.org/10.1002/dta.2813DOI Listing
August 2020

Active transport of rhodamine 123 by the human multidrug transporter P-glycoprotein involves two independent outer gates.

Pharmacol Res Perspect 2020 04;8(2):e00572

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

Human P-glycoprotein (P-gp) is a multispecific drug-efflux transporter, which plays an important role in drug resistance and drug disposition. Recent cryo-electron microscopy structures confirmed its rotationally symmetric architecture, which allows dual interaction with ATP and substrates. We here report the existence of two distinct, symmetry-related outer gates. Experiments were aided by availability of the X-ray structure of a homodimeric eukaryotic homolog of P-gp from red alga (CmABCB1), which defined the role of an apical tyrosine residue (Y358) in outer gate formation. We mutated analogous tyrosine residues in each half of the human full-length transporter (Y310, Y953) to alanine. These mutants were introduced in engineered transporters which bind rhodamine 123 in one of two symmetry-related binding modes only. Outer gate dysfunction was detected by a loss of active transport characteristics, while these mutants retained the ability for outward downhill transport. Our data demonstrate that symmetric tyrosine residues Y310 and Y953 are involved in formation of two distinct symmetry-related outer gates, which operate contingent on the rhodamine 123 binding mode. Hence, the rotationally symmetric architecture of P-gp, which determines duality in ATP binding and rhodamine 123 interaction, also forms the basis for the existence of two independently operating outer gates.
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http://dx.doi.org/10.1002/prp2.572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105846PMC
April 2020

A critical examination of the main premises of Traditional Chinese Medicine.

Wien Klin Wochenschr 2020 May 20;132(9-10):260-273. Epub 2020 Mar 20.

Institute of Pharmacology, Medical University Vienna, Vienna, Austria.

Traditional Chinese Medicine (TCM) consists of a plethora of therapeutic approaches aiming to both characterize and treat diseases. Its utilization has gained significant popularity in the western world and is even backed by the World Health Organization's decision to include TCM diagnostic patterns into the new revision of the International Classification of Diseases code, the global standard for diagnostic health information. As these developments and potentially far-reaching decisions can affect modern healthcare systems and daily clinical work as well as wildlife conservation, its underlying factual basis must be critically examined. This article therefore provides an overview of the evidence underlying the basic TCM concepts, such as Qi, meridians, acupuncture, pulse and tongue diagnostics as well as traditional herbal treatments. Moreover, it discusses whether scientific literature on TCM reflects the current standard for evidence-based research, as described in good scientific practice and good clinical practice guidelines. Importantly, misinformation regarding the therapeutic efficacy of animal-derived substances has lead and currently leads to problems with wildlife preservation and animal ethics. Nevertheless, the (re-)discovery of artemisinin more than 50 years ago introduced a novel development in TCM: the commingling of Eastern and Western medicine, the appreciation of both systems. The need for more rigorous approaches, fulfilment of and agreement to current guidelines to achieve high-quality research are of utmost relevance. Thereby, ancient knowledge of herbal species and concoctions may serve as a possible treasure box rather than Pandora's box.
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http://dx.doi.org/10.1007/s00508-020-01625-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253514PMC
May 2020

Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and impact.

J Biol Chem 2020 04 4;295(16):5229-5244. Epub 2020 Mar 4.

Brudnick Neuropsychiatric Research Institute, Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address:

Following its evoked release, dopamine (DA) signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DA transporter (DAT). DAT surface availability is dynamically regulated by endocytic trafficking, and direct protein kinase C (PKC) activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals or whether there are region- and/or sex-dependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKC-stimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation and that the DAT N terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in DAergic terminals.
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http://dx.doi.org/10.1074/jbc.RA120.012628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170531PMC
April 2020

On the relationship of first-episode psychosis to the amphetamine-sensitized state: a dopamine D receptor agonist radioligand study.

Transl Psychiatry 2020 01 8;10(1). Epub 2020 Jan 8.

Department of Psychiatry and Psychotherapy, Division of General Psychiatry, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Schizophrenia is characterized by increased behavioral and neurochemical responses to dopamine-releasing drugs. This prompted the hypothesis of psychosis as a state of "endogenous" sensitization of the dopamine system although the exact basis of dopaminergic disturbances and the possible role of prefrontal cortical regulation have remained uncertain. To show that patients with first-episode psychosis release more dopamine upon amphetamine-stimulation than healthy volunteers, and to reveal for the first time that prospective sensitization induced by repeated amphetamine exposure increases dopamine-release in stimulant-naïve healthy volunteers to levels observed in patients, we collected data on amphetamine-induced dopamine release using the dopamine D receptor agonist radioligand [C]-(+)-PHNO and positron emission tomography. Healthy volunteers (n = 28, 14 female) underwent a baseline and then a post-amphetamine scan before and after a mildly sensitizing regimen of repeated oral amphetamine. Unmedicated patients with first-episode psychosis (n = 21; 6 female) underwent a single pair of baseline and then post-amphetamine scans. Furthermore, T1 weighted magnetic resonance imaging of the prefrontal cortex was performed. Patients with first-episode psychosis showed larger release of dopamine compared to healthy volunteers. After sensitization of healthy volunteers their dopamine release was significantly amplified and no longer different from that seen in patients. Healthy volunteers showed a negative correlation between prefrontal cortical volume and dopamine release. There was no such relationship after sensitization or in patients. Our data in patients with untreated first-episode psychosis confirm the "endogenous sensitization" hypothesis and support the notion of impaired prefrontal control of the dopamine system in schizophrenia.
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http://dx.doi.org/10.1038/s41398-019-0681-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026156PMC
January 2020

The Amino Terminus of LeuT Changes Conformation in an Environment Sensitive Manner.

Neurochem Res 2020 Jun 19;45(6):1387-1398. Epub 2019 Dec 19.

Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Waehringerstr. 13a, 1090, Vienna, Austria.

Neurotransmitter:sodium symporters are highly expressed in the human brain and catalyze the uptake of substrate through the plasma membrane by using the electrochemical gradient of sodium as the energy source. The bacterial homolog LeuT, a small amino acid transporter isolated from the bacteria Aquifex aeolicus, is the founding member of the family and has been crystallized in three conformations. The N-terminus is structurally well defined and strongly interacts with the transporter core in the outward-facing conformations. However, it could not be resolved in the inward-facing conformation, which indicates enhanced mobility. Here we investigate conformations and dynamics of the N-terminus, by combining molecular dynamics simulations with experimental verification using distance measurements and accessibility studies. We found strongly increased dynamics of the N-terminus, but also that helix TM1A is subject to enhanced mobility. TM1A moves towards the transporter core in the membrane environment, reaching a conformation that is closer to the structure of LeuT with wild type sequence, indicating that the mutation introduced to create the inward-facing structure might have altered the position of helix TM1A. The mobile N-terminus avoids entering the open vestibule of the inward-facing state, as accessibility studies do not show any reduction of quenching by iodide of a fluorophore attached to the N-terminus.
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http://dx.doi.org/10.1007/s11064-019-02928-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260283PMC
June 2020

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

J Med Chem 2020 01 30;63(1):391-417. Epub 2019 Dec 30.

Neuroscience Laboratory , Paracelsus Medical University , A-5020 Salzburg , Austria.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships. Introduction of the second chiral center and subsequent chiral separations provided all four stereoisomers, whereby the -configuration on both generally exerted the highest activity and selectivity on DAT. The representative compound of this series was further characterized by , , and studies that have demonstrated both safety and efficacy profile of this compound class.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01938DOI Listing
January 2020

para-Trifluoromethyl-methcathinone is an allosteric modulator of the serotonin transporter.

Neuropharmacology 2019 12 24;161:107615. Epub 2019 Apr 24.

Institute of Pharmacology, Medical University, Vienna, Austria. Electronic address:

The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (pCFMCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the pCFgroup, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that pCFMCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.04.021DOI Listing
December 2019

Methamphetamine ("crystal meth") causes induction of DNA damage and chromosomal aberrations in human derived cells.

Food Chem Toxicol 2019 Jun 22;128:1-7. Epub 2019 Mar 22.

Institute of Cancer Research, Department of Internal Medicine 1, Medical University of Vienna, Vienna, Austria. Electronic address:

Methamphetamine (METH) is a widely consumed psychostimulant drug; its acute toxic effects in brain and liver are well known, furthermore, there is some evidence in regard to its DNA damaging properties in humans. Therefore, we studied the impact of the drug on genomic stability in human derived hepatoma (HepG2) cells, which reflect the activation/detoxification of drugs better than other cell lines. Furthermore, experiments with human buccal derived cells (TR146) were conducted as the drug is consumed orally. Induction of DNA damage in both cell types with doses reflecting the exposure in abusers was found in single cell gel electrophoresis (SCGE) assays (which detect single and double strand breaks as well as apurinic sites). Furthermore, induction of micronuclei (formed as a consequence of structural and numerical chromosomal aberrations) and formation of nuclear buds resulting from gene amplifications was detected. Additional experiments with lesion-specific enzymes showed that the drug causes oxidation of purines and pyrimidines, indicating that its genotoxic effects may be due to oxidation of the DNA. Our findings support the assumption that the drug may cause adverse health effects (such as cancer and infertility) in long-term users which are causally related to DNA damage.
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http://dx.doi.org/10.1016/j.fct.2019.03.035DOI Listing
June 2019

α-Fluorination of carbonyls with nucleophilic fluorine.

Nat Chem 2019 04 4;11(4):329-334. Epub 2019 Mar 4.

Institute of Organic Chemistry, University of Vienna, Vienna, Austria.

Given the unique properties of fluorine, and the ability of fluorination to change the properties of organic molecules, there is significant interest from medicinal chemists in innovative methodologies that enable the synthesis of new fluorinated motifs. State-of-the-art syntheses of α-fluorinated carbonyl compounds invariably rely on electrophilic fluorinating agents, which can be strongly oxidizing and difficult to handle. Here we show that reversing the polarity of the enolate partner to that of an enolonium enables nucleophilic fluorinating agents to be used for direct chemoselective α-C-H-fluorination of amides. Reduction of these products enables facile access to β-fluorinated amines and the value of this methodology is shown by the easy preparation of a number of fluorinated analogues of drugs and agrochemicals. A fluorinated analogue of citalopram, a marketed antidepressant drug, is presented as an example of the preserved biological activity after fluorination.
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http://dx.doi.org/10.1038/s41557-019-0215-zDOI Listing
April 2019

Structural, functional, and behavioral insights of dopamine dysfunction revealed by a deletion in .

Proc Natl Acad Sci U S A 2019 02 12;116(9):3853-3862. Epub 2019 Feb 12.

Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233;

The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N336). We uncovered that the deletion promoted a previously unobserved conformation of the intracellular gate of the transporter, likely representing the rate-limiting step of the transport process. It is defined by a "half-open and inward-facing" state (HOIF) of the intracellular gate that is stabilized by a network of interactions conserved phylogenetically, as we demonstrated in hDAT by Rosetta molecular modeling and fine-grained simulations, as well as in its bacterial homolog leucine transporter by electron paramagnetic resonance analysis and X-ray crystallography. The stabilization of the HOIF state is associated both with DA dysfunctions demonstrated in isolated brains of expressing hDAT ∆N336 and with abnormal behaviors observed at high-time resolution. These flies display increased fear, impaired social interactions, and locomotion traits we associate with DA dysfunction and the HOIF state. Together, our results describe how a genetic variation causes DA dysfunction and abnormal behaviors by stabilizing a HOIF state of the transporter.
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http://dx.doi.org/10.1073/pnas.1816247116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397532PMC
February 2019

Dopamine transporter forms stable dimers in the live cell plasma membrane in a phosphatidylinositol 4,5-bisphosphate-independent manner.

J Biol Chem 2019 04 31;294(14):5632-5642. Epub 2019 Jan 31.

From the Institute of Applied Physics, TU Wien, Getreidemarkt 9, A-1060, Vienna and

The human dopamine transporter (hDAT) regulates the level of the neurotransmitter dopamine (DA) in the synaptic cleft and recycles DA for storage in the presynaptic vesicular pool. Many neurotransmitter transporters exist as oligomers, but the physiological role of oligomerization remains unclear; for example, it has been speculated to be a prerequisite for amphetamine-induced release and protein trafficking. Previous studies point to an oligomeric quaternary structure of hDAT; however, the exact stoichiometry and the fraction of co-existing oligomeric states are not known. Here, we used single-molecule brightness analysis to quantify the degree of oligomerization of heterologously expressed hDAT fused to monomeric GFP (mGFP-hDAT) in Chinese hamster ovary (CHO) cells. We observed that monomers and dimers of mGFP-hDAT co-exist and that higher-order molecular complexes of mGFP-hDAT are absent at the plasma membrane. The mGFP-hDAT dimers were stable over several minutes, and the fraction of dimers was independent of the mGFP-hDAT surface density. Furthermore, neither oxidation nor depletion of cholesterol had any effect on the fraction of dimers. Unlike for the human serotonin transporter (hSERT), in which direct binding of phosphatidylinositol 4,5-bisphosphate (PIP) stabilized the oligomers, the stability of mGFP-hDAT dimers was PIP independent.
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http://dx.doi.org/10.1074/jbc.RA118.006178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462504PMC
April 2019

Stereochemistry of phase-1 metabolites of mephedrone determines their effectiveness as releasers at the serotonin transporter.

Neuropharmacology 2019 04 2;148:199-209. Epub 2019 Jan 2.

Medical University of Vienna, Center for Physiology and Pharmacology, Institute of Pharmacology, Vienna, Austria; Center for Addiction Research and Science - AddRess, Medical University Vienna, Waehringerstrasse 13A, 1090 Vienna, Austria. Electronic address:

Mephedrone (4-methyl-N-methylcathinone) is a psychostimulant that promotes release of monoamines via the high affinity transporters for dopamine (DAT), norepinephrine (NET) and serotonin (SERT). Metabolic breakdown of mephedrone results in bioactive metabolites that act as substrate-type releasers at monoamine transporters and stereospecific metabolism of mephedrone has been reported. This study compared the effects of the enantiomers of the phase-1 metabolites nor-mephedrone, 4-hydroxytolyl-mephedrone (4-OH-mephedrone) and dihydro-mephedrone on (i) DAT, NET and SERT mediated substrate fluxes, (ii) determined their binding affinities towards a battery of monoamine receptors and (iii) examined the relative abundance of the enantiomers in human urine. Each of the enantiomers tested inhibited uptake mediated by DAT, NET and SERT. No marked differences were detected at DAT and NET. However, at SERT, the S-enantiomers of nor-mephedrone and 4-OH-mephedrone were several times more potent than the corresponding R-enantiomers. Moreover, the R-enantiomers were markedly less effective as releasers at SERT. S-nor-mephedrone displayed moderate affinities towards human alpha, human 5-HT and rat and mouse trace amine-associated receptor 1. These results demonstrate that stereochemistry dictates the pharmacodynamics of the phase-1 metabolites of mephedrone at SERT, but not at DAT and NET, which manifests in marked differences in their relative potencies, i.e. DAT/SERT ratios. Chiral analysis of urine samples demonstrated that nor-mephedrone predominantly exists as the S-enantiomer. Given the asymmetric abundance of the enantiomers in biological samples, these findings may add to our understanding of the subjective effects of administered mephedrone, which indicate pronounced effects on the serotonergic system.
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http://dx.doi.org/10.1016/j.neuropharm.2018.12.032DOI Listing
April 2019

Dephosphorylation of human dopamine transporter at threonine 48 by protein phosphatase PP1/2A up-regulates transport velocity.

J Biol Chem 2019 03 26;294(10):3419-3431. Epub 2018 Dec 26.

the Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota 58202-9037, and

Several protein kinases, including protein kinase C, Ca/calmodulin-dependent protein kinase II, and extracellular signal-regulated kinase, play key roles in the regulation of dopamine transporter (DAT) functions. These functions include surface expression, internalization, and forward and reverse transport, with phosphorylation sites for these kinases being linked to distinct regions of the DAT N terminus. Protein phosphatases (PPs) also regulate DAT activity, but the specific residues associated with their activities have not yet been elucidated. In this study, using co-immunoprecipitation followed by MS and immunoblotting analyses, we demonstrate the association of DAT with PP1 and PP2A in the mouse brain and heterologous cell systems. By applying MS in conjunction with a metabolic labeling method, we defined a PP1/2A-sensitive phosphorylation site at Thr-48 in human DAT, a residue that has not been previously reported to be involved in DAT phosphorylation. Site-directed mutagenesis of Thr-48 to Ala (T48A) to prevent phosphorylation enhanced dopamine transport kinetics, supporting a role for this residue in regulating DAT activity. Moreover, T48A-DAT displayed increased palmitoylation, suggesting that phosphorylation/dephosphorylation at this site has an additional regulatory role and reinforcing a previously reported reciprocal relationship between C-terminal palmitoylation and N-terminal phosphorylation.
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http://dx.doi.org/10.1074/jbc.RA118.005251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416449PMC
March 2019

Isolation of synaptic vesicles from genetically engineered cultured neurons.

J Neurosci Methods 2019 01 26;312:114-121. Epub 2018 Nov 26.

Institute of Science and Technology Austria (IST Austria), Am Campus 1, 3400 Klosterneuburg, Austria; Australian Regenerative Medicine Institute (ARMI), Faculty of Medicine, Nursing and Health Sciences, Monash University, 15 Innovation Walk, Clayton, Melbourne, VIC 3800, Australia; European Molecular Biology Laboratory Australia (EMBL Australia), Monash University, 15 Innovation Walk, Clayton, Melbourne, VIC 3800, Australia. Electronic address:

Background: Synaptic vesicles (SVs) are an integral part of the neurotransmission machinery, and isolation of SVs from their host neuron is necessary to reveal their most fundamental biochemical and functional properties in in vitro assays. Isolated SVs from neurons that have been genetically engineered, e.g. to introduce genetically encoded indicators, are not readily available but would permit new insights into SV structure and function. Furthermore, it is unclear if cultured neurons can provide sufficient starting material for SV isolation procedures.

New Method: Here, we demonstrate an efficient ex vivo procedure to obtain functional SVs from cultured rat cortical neurons after genetic engineering with a lentivirus.

Results: We show that ∼10 plated cortical neurons allow isolation of suitable SV amounts for functional analysis and imaging. We found that SVs isolated from cultured neurons have neurotransmitter uptake comparable to that of SVs isolated from intact cortex. Using total internal reflection fluorescence (TIRF) microscopy, we visualized an exogenous SV-targeted marker protein and demonstrated the high efficiency of SV modification.

Comparison With Existing Methods: Obtaining SVs from genetically engineered neurons currently generally requires the availability of transgenic animals, which is constrained by technical (e.g. cost and time) and biological (e.g. developmental defects and lethality) limitations.

Conclusions: These results demonstrate the modification and isolation of functional SVs using cultured neurons and viral transduction. The ability to readily obtain SVs from genetically engineered neurons will permit linking in situ studies to in vitro experiments in a variety of genetic contexts.
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http://dx.doi.org/10.1016/j.jneumeth.2018.11.018DOI Listing
January 2019

Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter.

Eur J Pharmacol 2019 Jan 25;842:351-364. Epub 2018 Oct 25.

Department of Cellular & Integrative Physiology, University of Texas Health Science Center at San Antonio, United States; Department of Pharmacology, University of Texas Health Science Center at San Antonio, United States. Electronic address:

Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [H]citalopram, [H]nisoxetine and [H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders.
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http://dx.doi.org/10.1016/j.ejphar.2018.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440482PMC
January 2019

Neuropharmacology of Synthetic Cathinones.

Handb Exp Pharmacol 2018;252:113-142

Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.

Synthetic cathinones are derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant Catha edulis. Cathinone is the β-keto analog of amphetamine, and all synthetic cathinones display a β-keto moiety in their structure. Several synthetic cathinones are widely prescribed medications (e.g., bupropion, Wellbutrin), while others are problematic drugs of abuse (e.g., 4-methylmethcathinone, mephedrone). Similar to amphetamines, synthetic cathinones are psychomotor stimulants that exert their effects by impairing the normal function of plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and 5-HT (SERT). Ring-substituted cathinones like mephedrone are transporter substrates that evoke neurotransmitter release by reversing the normal direction of transporter flux (i.e., releasers), whereas pyrrolidine-containing cathinones like 3,4-methylenedioxypyrovalerone (MDPV) are potent transporter inhibitors that block neurotransmitter uptake (i.e., blockers). Regardless of molecular mechanism, all synthetic cathinones increase extracellular monoamine concentrations in the brain, thereby enhancing cell-to-cell monoamine signaling. Here, we briefly review the mechanisms of action, structure-activity relationships, and in vivo pharmacology of synthetic cathinones. Overall, the findings show that certain synthetic cathinones are powerful drugs of abuse that could pose significant risk to users.
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http://dx.doi.org/10.1007/164_2018_178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257813PMC
June 2019

The synthetic cathinones, butylone and pentylone, are stimulants that act as dopamine transporter blockers but 5-HT transporter substrates.

Psychopharmacology (Berl) 2019 Mar 22;236(3):953-962. Epub 2018 Oct 22.

Designer Drug Research Unit (DDRU), Intramural Research Program (IRP), NIDA, NIH, DHHS, 333 Cassell Drive, Suite 4400, Baltimore, MD, 21224, USA.

Rationale: Synthetic cathinones continue to emerge in recreational drug markets worldwide. 1-(1,3-Benzodioxol-5-yl)-2-(methylamino)butan-1-one (butylone) and 1-(1,3-benzodioxol-5-yl)-2-(methylamino)pentan-1-one (pentylone) are derivatives of the cathinone compound, 1-(1,3-benzodioxol-5-yl)-2-(methylamino)propan-1-one (methylone), that are being detected in drug products and human casework.

Objectives: The purpose of the present study was to examine the neuropharmacology of butylone and pentylone using in vitro and in vivo methods.

Methods: In vitro uptake and release assays were carried out in rat brain synaptosomes and in cells expressing human dopamine transporters (DAT) and 5-HT transporters (SERT). In vivo microdialysis was performed in the nucleus accumbens of conscious rats to assess drug-induced changes in neurochemistry.

Results: Butylone and pentylone were efficacious uptake blockers at DAT and SERT, though pentylone was more DAT-selective. Both drugs acted as transporter substrates that evoked release of [H]5-HT at SERT, while neither evoked release at DAT. Consistent with the release data, butylone and pentylone induced substrate-associated inward currents at SERT but not DAT. Administration of butylone or pentylone to rats (1 and 3 mg/kg, i.v.) increased extracellular monoamines and motor activity, but pentylone had weaker effects on 5-HT and stronger effects on motor stimulation.

Conclusions: Our data demonstrate that increasing the α-carbon chain length of methylone creates "hybrid" transporter compounds which act as DAT blockers but SERT substrates. Nevertheless, butylone and pentylone elevate extracellular dopamine and stimulate motor activity, suggesting both drugs possess significant risk for abuse.
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http://dx.doi.org/10.1007/s00213-018-5075-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476708PMC
March 2019

DARK Classics in Chemical Neuroscience: Aminorex Analogues.

ACS Chem Neurosci 2018 10 5;9(10):2484-2502. Epub 2018 Oct 5.

Center for Physiology and Pharmacology, Institute of Pharmacology , Medical University of Vienna , Währingerstraße 13A , 1090 Vienna , Austria.

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 analogues exist that are not internationally controlled and therefore often classified as new psychoactive substances (NPS). Aminorex analogues 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 analogues. 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.
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http://dx.doi.org/10.1021/acschemneuro.8b00415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287711PMC
October 2018