Search

Copyright of Acta physica Academiae Scientiarum Hungaricae is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Examination of 18 males by graded load in the step-test and on the bicycle ergomotor showed the following. Both tasks carried on to exhaustion gave practically the same heart rate values, the performance and oxygen intake being different. The maximum oxygen intake in the step-test was on an average 0·33 1/min (11 percent) lower than that on the ergometer. The differences were more pronounced and statistically significant in the younger subjects tested. The same applied, to a greater extent, to the values of the maximum output of carbon dioxide. The logarithms of values of oxygen intake or heart rate at different grades of load using both tests are linearly related to the logarithms of the corresponding values of lactic acid. The correlation coefficients for these relations are statistically highly significant. [ABSTRACT FROM PUBLISHER]

Ferroelectric tunnel junctions (FTJs) are a class of memristor which promise low-power, scalable, field-driven analog operation. In order to harness their full potential, operation with identical pulses is targeted. In this paper, several weight update schemes for FTJs are investigated, using either nonidentical or identical pulses, and with time delays between the pulses ranging from 1 μs to 10 s. Experimentally, a method for achieving nonlinear weight update with identical pulses at long programming delays is demonstrated by limiting the switching current via a series resistor. Simulations show that this concept can be expanded to achieve weight update in a 1T1C cell by limiting the switching current through a transistor operating in subthreshold or saturation mode. This leads to a maximum linearity in the weight update of 86% for a dynamic range (maximum switched polarization) of 30 μC/cm 2 . It is further demonstrated via simulation that engineering the device to achieve a narrower switching peak increases the linearity in scaled devices to >93% for the same range.

Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids - termed oxa-iboga - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential., (© 2024. The Author(s).)

Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders 1-3 . These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT 2A (ref. 4 ). However, 5-HT 1A also plays a part in the behavioural effects of tryptamine hallucinogens 5 , particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads 6 . Although 5-HT 1A is a validated therapeutic target 7,8 , little is known about how psychedelics engage 5-HT 1A and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT 1A , systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT 1A and 5-HT 2A enable the characterization of molecular determinants of 5-HT 1A signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT 1A agonists. We show that a 5-HT 1A -selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT 1A -targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material "kratom", which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 position of the MG scaffold (C6 position in indole numbering) via the use of an indole-ethylene glycol adduct and subsequent iridium-catalyzed borylation. Through this work we discover that C11 represents a key locant for fine-tuning opioid receptor signaling efficacy. 7-Hydroxymitragynine (7OH), the parent compound with low efficacy on par with buprenorphine, is transformed to an even lower efficacy agonist by introducing a fluorine substituent in this position (11-F-7OH), as demonstrated in vitro at both mouse and human mu opioid receptors (mMOR/hMOR) and in vivo in mouse analgesia tests. Low efficacy opioid agonists are of high interest as candidates for generating safer opioid medications with mitigated adverse effects.

The increasing demand for high-density data storage leads to an increasing interest in novel memory concepts with high scalability and the opportunity of storing multiple bits in one cell. A promising candidate is the redox-based resistive switch repositing the information in form of different resistance states. For reliable programming, the underlying physical parameters need to be understood. We reveal that the programmable resistance states are linked to internal series resistances and the fundamental nonlinear switching kinetics. The switching kinetics of [Formula: see text]-based cells was investigated in a wide range over 15 orders of magnitude from 10[Formula: see text] s to 250 ps. The capacitive charging time of our device limits the direct observation of the set time below 770 ps, however, we found indication for an intrinsic switching speed of 10 ps at a stimulus of 3 V. On all time scales, multi-bit data storage capabilities were demonstrated. The elucidated link between fundamental material properties and multi-bit data storage paves the way for designing resistive switches for memory and neuromorphic applications.

Anecdotal reports and open-label case studies in humans indicated that the psychedelic alkaloid ibogaine exerts profound antiaddictive effects. Ample preclinical evidence demonstrated the efficacy of ibogaine, and its main metabolite, noribogaine, in substance-use-disorder rodent models. In contrast to addiction research, depression-relevant effects of ibogaine or noribogaine in rodents have not been previously examined. We have recently reported that the acute ibogaine administration induced a long-term increase of brain-derived neurotrophic factor mRNA levels in the rat prefrontal cortex, which led us to hypothesize that ibogaine may elicit antidepressant-like effects in rats. Accordingly, we characterized behavioral effects (dose- and time-dependence) induced by the acute ibogaine and noribogaine administration in rats using the forced swim test (FST, 20 and 40 mg/kg i.p., single injection for each dose). We also examined the correlation between plasma and brain concentrations of ibogaine and noribogaine and the elicited behavioral response. We found that ibogaine and noribogaine induced a dose- and time-dependent antidepressant-like effect without significant changes of animal locomotor activity. Noribogaine's FST effect was short-lived (30 min) and correlated with high brain concentrations (estimated >8 μM of free drug), while the ibogaine's antidepressant-like effect was significant at 3 h. At this time point, both ibogaine and noribogaine were present in rat brain at concentrations that cannot produce the same behavioral outcome on their own (ibogaine ∼0.5 μM, noribogaine ∼2.5 μM). Our data suggests a polypharmacological mechanism underpinning the antidepressant-like effects of ibogaine and noribogaine.

Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors. The proof of principle was demonstrated on rotaxane synthesis, with near-quantitative yields observed in both the classical and "in situ" approach. The rotaxane formation was confirmed in the solid-state and solution by the X-ray and NMR studies. Our novel approach could be utilized in the fields of dynamic combinatorial chemistry, supramolecular polymers, or molecular machines, as well inspire further research on molecules that exhibit dynamic behavior, but owing to their high reactivity, have not been considered as constituents of more elaborate supramolecular structures., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In contrast to classical charge-based memories, the binary information in redox-based resistive switching devices is decoded by a change of the atomic configuration rather than changing the amount of stored electrons. This offers in principle a higher scaling potential as ions are not prone to tunneling and the information is not lost by tunneling. The switching speed, however, is potentially smaller since the ionic mass is much higher than the electron mass. In this work, the ultimate switching speed limit of redox-based resistive switching devices is discussed. Based on a theoretical analysis of the underlying physical processes, it is derived that the switching speed is limited by the phonon frequency. This limit is identical when considering the acceleration of the underlying processes by local Joule heating or by high electric fields. Electro-thermal simulations show that a small filamentary volume can be heated up in picoseconds. Likewise, the characteristic charging time of a nanocrossbar device can be even below ps. In principle, temperature and voltage can be brought fast enough to the device to reach the ultimate switching limit. In addition, the experimental route and the challenges towards reaching the ultimate switching speed limit are discussed. So far, the experimental switching speed is limited by the measurement setup.

The accumulated knowledge regarding molecular architectures is based on established, reliable, and accessible analytical tools that provide robust structural and functional information on assemblies. However, both the dynamicity and low population of noncovalently interacting moieties within studied molecular systems limit the efficiency and accuracy of traditional methods. Herein, the use of a saturation transfer-based NMR approach to study the dynamic binding characteristics of an anion to a series of synthetic receptors derived from bambusuril macrocycles is demonstrated. The exchange rates of BF 4 - are mediated by the side chains on the receptor (100 s -1 ex <5000 s -1 ), which play a critical role in receptor-anion binding dynamics. The signal amplification obtained with this approach allows for the identification of different types of intermolecular interactions between the receptor and the anion, something that could not have been detected by techniques hitherto used to study molecular assemblies. These findings, which are supported by a computational molecular dynamic study, demonstrate the uniqueness and added value of this NMR method., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new bambusuril derivative, (H)BU[6] , lacking substituents on the ureidic nitrogen atoms, has been isolated and characterized. This macrocycle was prepared by the deprotection of bambusuril (PMB)BU[6] . (H)BU[6] is attractive for use as a starting compound for the preparation of other bambusuril derivatives, which was demonstrated via propargylation and the copper-catalyzed click reaction performed on the macrocycle., Competing Interests: The authors declare no competing financial interest.