Coinductive subtyping for abstract compilation of object-oriented languages into Horn formulas

In recent work we have shown how it is possible to define very precise type systems for object-oriented languages by abstractly compiling a program into a Horn formula f. Then type inference amounts to resolving a certain goal w.r.t. the coinductive (that is, the greatest) Herbrand model of f. Type systems defined in this way are idealized, since in the most interesting instantiations both the terms of the coinductive Herbrand universe and goal derivations cannot be finitely represented. However, sound and quite expressive approximations can be implemented by considering only regular terms and derivations. In doing so, it is essential to introduce a proper subtyping relation formalizing the notion of approximation between types. In this paper we study a subtyping relation on coinductive terms built on union and object type constructors. We define an interpretation of types as set of values induced by a quite intuitive relation of membership of values to types, and prove that the definition of subtyping is sound w.r.t. subset inclusion between type interpretations. The proof of soundness has allowed us to simplify the notion of contractive derivation and to discover that the previously given definition of subtyping did not cover all possible representations of the empty type

Interactions of phenethylamine‐derived psychoactive substances of the 2C‐series with human monoamine oxidases

Psychoactive substances of the 2C‐series (2Cs) are phenethylamine‐derived designer drugs that can induce psychostimulant and hallucinogenic effects. Chemically, the classic 2Cs contain two methoxy groups in positions 2 and 5 of the phenyl ring, whereas substances of the so‐called FLY series contain rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b’]difuran core. One of the pharmacological features that has not been investigated in detail is the inhibition of monoamine oxidase (MAO). Inhibition of this enzyme can cause elevated monoamine levels that have been associated with adverse events such as agitation, nausea, vomiting, tachycardia, hypertension, or seizures. The aim of this study was to extend the knowledge surrounding the potential of MAO inhibition for 17 test drugs, which consisted of 12 2Cs (2C‐B, 2C‐D, 2C‐E, 2C‐H, 2C‐I, 2C‐N, 2C‐P, 2C‐T‐2, 2C‐T‐7, 2C‐T‐21, bk‐2C‐B, and bk‐2C‐I) and five FLY analogs (2C‐B‐FLY, 2C‐E‐FLY, 2C‐EF‐FLY, 2C‐I‐FLY, and 2C‐T‐7‐FLY). The extent of MAO inhibition was assessed using an established in vitro procedure based on heterologously expressed enzymes and analysis by hydrophilic interaction liquid chromatography–high resolution tandem mass spectrometry. Thirteen test drugs showed inhibition potential for MAO‐A and 11 showed inhibition of MAO‐B. In cases where MAO‐A IC50 values were determined, values ranged from 10 to 125 μM (7 drugs) and from 1.7 to 180 μM for MAO‐B (9 drugs). In the absence of detailed clinical information on most test drugs, it is concluded that a pharmacological contribution of MAO inhibition cannot be excluded and that further studies are warranted

In vitro monoamine oxidase inhibition potential of alpha-methyltryptamine analog new psychoactive substances for assessing possible toxic risks

Tryptamines have emerged as new psychoactive substances (NPS), which are distributed and consumed recreationally without preclinical studies or safety tests. Within the alpha-methylated tryptamines, some of the psychoactive effects of the prototypical alpha-methyltryptamine (AMT) have been described decades ago and a contributing factor of its acute toxicity appears to involve the inhibition of monoamine oxidase (MAO). However, detailed information about analogs is scarce. Therefore, thirteen AMT analogs were investigated for their potential to inhibit MAO. An in vitro assay analyzed using hydrophilic interaction liquid chromatography–high resolution-tandem mass spectrometry was developed and validated. The AMT analogs were incubated with recombinant human MAO-A or B and kynuramine, a non-selective MAO substrate to determine the IC50 values. The known MAO-A inhibitors 5-(2-aminopropyl)indole (5-IT), harmine, harmaline, yohimbine, and the MAO-B inhibitor selegiline were tested for comparison. AMT and all analogs showed MAO-A inhibition properties with IC50 values between 0.049 and 166 μM, whereas four analogs inhibited also MAO-B with IC50 values between 82 and 376 μM. 7-Me-AMT provided the lowest IC50 value against MAO-A comparable to harmine and harmaline and was identified as a competitive MAO-A inhibitor. Furthermore, AMT, 7-Me-AMT, and nine further analogs inhibited MAO activity in human hepatic S9 fraction used as model for the human liver which expresses both isoforms. The obtained results suggested that MAO inhibition induced by alpha-methylated tryptamines might be clinically relevant concerning possible serotonergic and adrenergic effects and interactions with drugs (of abuse) particularly acting as monoamine reuptake inhibitors. However, as in vitro assays have only limited conclusiveness, further studies are needed

In vitro metabolic fate of the synthetic cannabinoid receptor agonists (quinolin-8-yl 4-methyl-3-(morpholine-4-sulfonyl)benzoate [QMMSB]) and (quinolin-8-yl 4-methyl-3-((propan-2-yl)sulfamoyl)benzoate [QMiPSB]) including isozyme mapping and carboxylesterases activity testing

The synthetic cannabinoid receptor agonists (SCRAs) (quinolin-8-yl 4-methyl-3-(morpholine-4-sulfonyl)benzoate [QMMSB]) and (quinolin-8-yl 4-methyl-3-((propan-2-yl)sulfamoyl)benzoate [QMiPSB], also known as SGT-46) are based on the structure of quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) that has been identified on seized plant material in 2011. In clinical toxicology, knowledge of the metabolic fate is important for their identification in biosamples. Therefore, the aim of this study was the identification of in vitro Phase I and II metabolites of QMMSB and QMiPSB in pooled human liver S9 fraction (pHLS9) incubations for use as screening targets. In addition, the involvement of human monooxygenases and human carboxylesterases (hCES) was examined. Analyses were performed by liquid chromatography coupled with high-resolution tandem mass spectrometry. Ester hydrolysis was found to be an important step in the Phase I metabolism of both SCRAs, with the carboxylic acid product being found only in negative ionization mode. Monohydroxy and N-dealkyl metabolites of the ester hydrolysis products were detected as well as glucuronides. CYP2C8, CYP2C9, CYP3A4, and CYP3A5 were involved in hydroxylation. Whereas enzymatic ester hydrolysis of QMiPSB was mainly catalyzed by hCES1 isoforms, nonenzymatic ester hydrolysis was also observed. The results suggest that ester hydrolysis products of QMMSB and QMiPSB and their glucuronides are suitable targets for toxicological screenings. The additional use of the negative ionization mode is recommended to increase detectability of analytes. Different cytochrome P450 (CYP) isozymes were involved in the metabolism; thus, the probability of drug–drug interactions due to CYP inhibition can be assessed as low

Phenethylamine-derived new psychoactive substances 2C-E-FLY, 2C-EF-FLY, and 2C-T-7-FLY: Investigations on their metabolic fate including isoenzyme activities and their toxicological detectability in urine screenings

Psychoactive substances of the 2C‐series are phenethylamine‐based designer drugs that can induce psychostimulant and hallucinogenic effects. The so‐called 2C‐FLY series contains rigidified methoxy groups integrated in a 2,3,6,7‐tetrahydrobenzo[1,2‐b:4,5‐b']difuran core. The aim of the presented work was to investigate the in vivo and in vitro metabolic fate including isoenzyme activities and toxicological detectability of the three new psychoactive substances (NPS) 2C‐E‐FLY, 2C‐EF‐FLY, and 2C‐T‐7‐FLY to allow clinical and forensic toxicologists the identification of these novel compounds. Rat urine, after oral administration, and pooled human liver S9 fraction (pS9) incubations were analyzed by liquid chromatography−high‐resolution tandem mass spectrometry (LC−HRMS/MS). By performing activity screenings, the human isoenzymes involved were identified and toxicological detectability in rat urine investigated using standard urine screening approaches (SUSAs) based on gas chromatography (GC)−MS, LC−MSn, and LC−HRMS/MS. In total, 32 metabolites were tentatively identified. Main metabolic steps consisted of hydroxylation and N‐acetylation. Phase I metabolic reactions were catalyzed by CYP2D6, 3A4, and FMO3 and N‐acetylation by NAT1 and NAT2. Methoxyamine was used as a trapping agent for detection of the deaminated metabolite formed by MAO‐A and B. Interindividual differences in the metabolism of the 2C‐FLY drugs could be caused by polymorphisms of enzymes involved or drug–drug interactions. All three SUSAs were shown to be suitable to detect an intake of these NPS but common metabolites of 2C‐E‐FLY and 2C‐EF‐FLY have to be considered during interpretation of analytical findings

In vitro metabolic fate of nine LSD-based new psychoactive substances and their analytical detectability in different urinary screening procedures

The market of new psychoactive substances (NPS) is characterized by a high turnover and thus provides several challenges for analytical toxicology. The analysis of urine samples often requires detailed knowledge about metabolism given that parent compounds either may be present only in small amounts or may not even be excreted. Hence, knowledge of the metabolism of NPS is a prerequisite for the development of reliable analytical methods. The main aim of this work was to elucidate for the first time the pooled human liver S9 fraction metabolism of the nine d-lysergic acid diethylamide (LSD) derivatives 1-acetyl-LSD (ALD-52), 1-propionyl-LSD (1P-LSD), 1-butyryl-LSD (1B-LSD), N6-ethyl-nor-LSD (ETH-LAD), 1-propionyl-N6-ethyl-nor-LSD (1P-ETH-LAD), N6-allyl-nor-LSD (AL-LAD), N-ethyl-N-cyclopropyl lysergamide (ECPLA), (2′S,4′S)-lysergic acid 2,4-dimethylazetidide (LSZ), and lysergic acid morpholide (LSM-775) by means of liquid chromatography coupled to high-resolution tandem mass spectrometry. Identification of the monooxygenase enzymes involved in the initial metabolic steps was performed using recombinant human enzymes and their contribution confirmed by inhibition experiments. Overall, N-dealkylation and hydroxylation, as well as combinations of these steps predominantly catalyzed by CYP1A2 and CYP3A4, were found. For ALD-52, 1P-LSD, and 1B-LSD, deacylation to LSD was observed. The obtained mass spectral data of all metabolites are essential for reliable analytical detection particularly in urinalysis and for differentiation of the LSD-like compounds as biotransformations also led to structurally identical metabolites. However, in urine of rats after the administration of expected recreational doses and using standard urine screening approaches, parent drugs or metabolites could not be detected

Ephenidine:A new psychoactive agent with ketamine-like NMDA receptor antagonist properties

To avoid legislation based on chemical structure, research chemicals, frequently used for recreational purposes, are continually being synthesized. N-Ethyl-1,2-diphenylethanamine (ephenidine) is a diarylethylamine that has recently become popular with recreational users searching for dissociative hallucinogenic effects. In the present study, the pharmacological basis of its neural actions has been investigated, initially by assessing its profile in central nervous system receptor binding assays and subsequently in targeted electrophysiological studies. Ephenidine was a potent inhibitor of 3H-MK-801 binding (Ki: 66 nM), implying that it acts at the PCP site of the N-methyl-d-aspartate (NMDA) receptor. It also showed modest activity at dopamine (379 nM) and noradrenaline (841 nM) transporters and at sigma 1 (629 nM) and sigma 2 (722 nM) binding sites. In experiments of extracellular recording of field excitatory postsynaptic potentials (fEPSPs) from area CA1 of rat hippocampal slices, ephenidine, 1 and 10 μM, respectively, produced a 25% and a near maximal inhibition of the NMDA receptor mediated fEPSP after 4 h superfusion. By contrast, ephenidine (50 μM) did not affect the AMPA receptor mediated fEPSPs. In whole cell patch clamp recordings, from hippocampal pyramidal cells, ephenidine (10 μM) blocked NMDA receptor-mediated EPSCs in a highly voltage-dependent manner. Additionally, ephenidine, 10 μM, blocked the induction of long term potentiation (LTP) in CA1 induced by theta burst stimulation. The present data show that the new psychoactive substance, ephenidine, is a selective NMDA receptor antagonist with a voltage-dependent profile similar to ketamine. Such properties help explain the dissociative, cognitive and hallucinogenic effects in man

Nonuniversal Correlations and Crossover Effects in the Bragg-Glass Phase of Impure Superconductors

The structural correlation functions of a weakly disordered Abrikosov lattice are calculated in a functional RG-expansion in $d=4-\epsilon$ dimensions. It is shown, that in the asymptotic limit the Abrikosov lattice exhibits still quasi-long-range translational order described by a {\it nonuniversal} exponent $\eta_{\bf G}$ which depends on the ratio of the renormalized elastic constants $\kappa ={c}_{66}/ {c}_{11}$ of the flux line (FL) lattice. Our calculations clearly demonstrate three distinct scaling regimes corresponding to the Larkin, the random manifold and the asymptotic Bragg-glass regime. On a wide range of {\it intermediate} length scales the FL displacement correlation function increases as a power law with twice the manifold roughness exponent $\zeta_{\rm RM}(\kappa)$, which is also {\it nonuniversal}. Correlation functions in the asymptotic regime are calculated in their full anisotropic dependencies and various order parameters are examined. Our results, in particular the $\kappa$-dependency of the exponents, are in variance with those of the variational treatment with replica symmetry breaking which allows in principle an experimental discrimination between the two approaches.Comment: 17 pages, 10 figure

The Gliese 86 Binary System: A Warm Jupiter Formed in a Disk Truncated at ≈2 au

© 2022. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/Gliese 86 is a nearby K dwarf hosting a giant planet on a ≈16 day orbit and an outer white dwarf companion on a ≈century-long orbit. In this study we combine radial velocity data (including new measurements spanning more than a decade) with high angular resolution imaging and absolute astrometry from Hipparcos and Gaia to measure the current orbits and masses of both companions. We then simulate the evolution of the Gl 86 system to constrain its primordial orbit when both stars were on the main sequence; the closest approach between the two stars was then about 9 au. Such a close separation limited the size of the protoplanetary disk of Gl 86 A and dynamically hindered the formation of the giant planet around it. Our measurements of Gl 86 B and Gl 86 Ab’s orbits reveal Gl 86 as a system in which giant planet formation took place in a disk truncated at ≈2 au. Such a disk would be just big enough to harbor the dust mass and total mass needed to assemble Gl 86 Ab’s core and envelope, assuming a high disk accretion rate and a low viscosity. Inefficient accretion of the disk onto Gl 86 Ab, however, would require a disk massive enough to approach the Toomre stability limit at its outer truncation radius. The orbital architecture of the Gl 86 system shows that giant planets can form even in severely truncated disks and provides an important benchmark for planet formation theory.Peer reviewe

The Gliese 86 Binary System: A Warm Jupiter Formed in a Disk Truncated at approximate to 2 au

Gliese 86 is a nearby K dwarf hosting a giant planet on a ≈16 day orbit and an outer white dwarf companion on a ≈century-long orbit. In this study we combine radial velocity data (including new measurements spanning more than a decade) with high angular resolution imaging and absolute astrometry from Hipparcos and Gaia to measure the current orbits and masses of both companions. We then simulate the evolution of the Gl 86 system to constrain its primordial orbit when both stars were on the main sequence; the closest approach between the two stars was then about 9 au. Such a close separation limited the size of the protoplanetary disk of Gl 86 A and dynamically hindered the formation of the giant planet around it. Our measurements of Gl 86 B and Gl 86 Ab’s orbits reveal Gl 86 as a system in which giant planet formation took place in a disk truncated at ≈2 au. Such a disk would be just big enough to harbor the dust mass and total mass needed to assemble Gl 86 Ab’s core and envelope, assuming a high disk accretion rate and a low viscosity. Inefficient accretion of the disk onto Gl 86 Ab, however, would require a disk massive enough to approach the Toomre stability limit at its outer truncation radius. The orbital architecture of the Gl 86 system shows that giant planets can form even in severely truncated disks and provides an important benchmark for planet formation theory