Membrane permeation of psychedelic tryptamines by dynamic simulations

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activityPID2020-117806GA-I0

Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT 2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT 2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity. </p

Characterization of the Binding Poses of Classical and Photoswitchable Psychedelics Interacting with 5-HT2AR

Classic psychedelics are compounds that target the 5-hydroxytryptamine receptor type 2A (5-HT2AR), inducing profound changes in consciousness. Although these compounds most closely resemble the natural neurotransmitter serotonin, their therapeutic and psychoactive action is still not well understood. Therefore, a quantitative atomistic description of their interaction in the 5-HT2AR receptor is required to shed light into their mode of action. In this work, we performed a computational characterization of the orthosteric binding pocket for classical and photoswitchable psychedelics by means of semi-flexible molecular docking, classical molecular dynamics and binding free energy computations to identify the interactions with the key protein residues. Two nearly degenerate binding poses were observed inside the orthosteric pocket. 5-HT (5-hydroxytryptamine) and LSD (lysergic acid diethylamide) show a preference for the canonical crystallized pose of the 5-HT2AR-LSD structure, in contrast to N,N-DMT (N,N-dimethyltryptamine) and 4-OH-N,N-DMT (4-hydroxy-N,N-dimethyltryptamine), which show a small preference for the newly identified pose. The photoswitchable analogs trans- and cis- AzobenzeneDMT (AzoDMT) interact similarly to N,N-DMT, with the cis-AzoDMT isomer being the most stable. Finally, the azobenzene domain of both cis- and trans-AzoDMT interact with the same key residue (L229) responsible for the extracellular loop closure of LSD. Our simulations clarify the nature of intermolecular drug/protein interactions, which can help to develop new classes of classical and photoswitchable psychedelics

Membrane Permeation of Psychedelic Compounds

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (5-HT2AR), psychedelics induce enduring neurophysiological changes which parallel their therapeutic psychological and behavioral effects. Recent pre-clinical evi- dence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2AR. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of twelve selected tryptamines and to characterize the interactions that drive the process. We elucidate the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Morevoer, there is a significant influence of positional substitutions on the indole groups and the protonation of the molecules substantially increase the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activit

Is REM sleep a paradoxical state?: Different neurons are activated in the cingulate cortices and the claustrum during wakefulness and paradoxical sleep hypersomnia

International audienceMichel Jouvet proposed in 1959 that REM sleep is a paradoxical state since it was characterized by the association of a cortical activation similar to wakefulness (W) with muscle atonia. Recently, we showed using cFos as a marker of activity that cortical activation during paradoxical sleep (PS) was limited to a few limbic cortical structures in contrast to W during which all cortices were strongly activated. However, we were not able to demonstrate whether the same neurons are activated during PS and W and to rule out that the activation observed was not linked with stress induced by the flowerpot method of PS deprivation. In the present study, we answered to these two questions by combining tdTomato and cFos immunostaining in the innovative TRAP2 transgenic mice exposed one week apart to two periods of W (W-W mice), PS rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR mice). Using such method, we showed that different neurons are activated during W and PSR in the anterior cingulate (ACA) and rostral and caudal retrosplenial (rRSP and cRSP) cortices as well as the claustrum (CLA) previously shown to contain a large number of activated neurons after PSR. Further, the distribution of the neurons during PSR in the rRSP and cRSP was limited to the superficial layers while it was widespread across all layers during W. Our results clearly show at the cellular level that PS and W are two completely different states in term of neocortical activation

Membrane Permeation of Psychedelic Tryptamines by Dynamic Simulations

Renewed scientific interest in psychedelic compounds represents one of the most promising avenues for addressing the current burden of mental health disorders. Classic psychedelics are a group of compounds that exhibit structural similarities to the naturally occurring neurotransmitter serotonin (5-HT). Acting on the 5-HT type 2A receptors (HT2ARs), psychedelics induce enduring neurophysiological changes that parallel their therapeutic psychological and behavioral effects. Recent preclinical evidence suggests that the ability of psychedelics to exert their action is determined by their ability to permeate the neuronal membrane to target a pool of intracellular 5-HT2ARs. In this computational study, we employ classical molecular dynamics simulations and umbrella sampling techniques to investigate the permeation behavior of 12 selected tryptamines and to characterize the interactions that drive the process. We aim at elucidating the impact of N-alkylation, indole ring substitution and positional modifications, and protonation on their membrane permeability. Dimethylation of the primary amine group and the introduction of a methoxy group at position 5 exhibited an increase in permeability. Moreover, there is a significant influence of positional substitutions on the indole groups, and the protonation of the molecules substantially increases the energy barrier at the center of the bilayer, making the compounds highly impermeable. All the information extracted from the trends predicted by the simulations can be applied in future drug design projects to develop psychedelics with enhanced activity

Granule cells in the infrapyramidal blade of the dentate gyrus are activated during paradoxical (REM) sleep hypersomnia but not during wakefulness: a study using TRAP mice

International audienceAbstract Objectives Determine whether in the hippocampus and the supramammillary nucleus (SuM) the same neurons are reactivated when mice are exposed 1 week apart to two periods of wakefulness (W-W), paradoxical sleep rebound (PSR-PSR) or a period of W followed by a period of PSR (W-PSR) Methods We combined the innovative TRAP2 mice method in which neurons expressing cFos permanently express tdTomato after tamoxifen injection with cFos immunohistochemistry. Results We found out that a large number of tdTomato+ and cFos+ cells are localized in the dentate gyrus (DG) after PSR and W while CA1 and CA3 contained both types of neurons only after W. The number of cFos+ cells in the infrapyramidal but not the suprapyramidal blade of the DG was positively correlated with the amount of PS. In addition, we did not find double-labeled cells in the DG whatever the group of mice. In contrast, a high percentage of CA1 neurons were double-labeled in W-W mice. Finally, in the supramammillary nucleus, a large number of cells were double-labeled in W-W, PSR-PSR but not in W-PSR mice. Conclusions Altogether, our results are the first to show that different neurons are activated during W and PS in the supramammillary nucleus and the hippocampus. Further, we showed for the first time that granule cells of the infrapyramidal blade of the DG are activated during PS but not during W. Further experiments are now needed to determine whether these granule cells belong to memory engrams inducing memory reactivation during PS

Data_Sheet_1_Safety, tolerability, pharmacodynamic and wellbeing effects of SPL026 (dimethyltryptamine fumarate) in healthy participants: a randomized, placebo-controlled phase 1 trial.docx

BackgroundDue to their potential impact on mood and wellbeing there has been increasing interest in the potential of serotonergic psychedelics such as N,N-dimethyltryptamine (DMT) in the treatment of major depressive disorder (MDD).AimThe aim of Part A of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) profile of escalating doses of SPL026 (DMT fumarate) in psychedelic-naïve healthy participants to determine a dose for administration to patients with MDD in the subsequent Phase 2a part of the trial (Part B: not presented in this manuscript).MethodsIn the Phase 1, randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naïve participants were randomized to placebo (n = 8) or four different escalating doses [9, 12, 17 and 21.5 mg intravenously (IV)] of SPL026 (n = 6 for each dose) together with psychological support from 2 therapy team members. PK and acute (immediately following dosing experience) psychometric measures [including mystical experience questionnaire (MEQ), ego dissolution inventory (EDI), and intensity rating visual analogue scale (IRVAS)] were determined. Additional endpoints were measured as longer-term change from baseline to days 8, 15, 30 and 90. These measures included the Warwick and Edinburgh mental wellbeing scale and Spielberger’s state-trait anxiety inventory.ResultsSPL026 was well tolerated, with an acceptable safety profile, with no serious adverse events. There was some evidence of a correlation between maximum plasma concentration and increased IRVAS, MEQ, and EDI scores. These trends are likely to require confirmation in a larger sample size. Using the analysis of the safety, tolerability, PD, PK results, doses of 21.5 mg SPL026 were the most likely to provide an intense, tolerated experience.ConclusionBased on the data obtained from this part of the trial, a dose of 21.5 mg SPL026 given as a 2-phase IV infusion over 10 min (6 mg/5 min and 15.5 mg/5 min) was selected as the dose to be taken into patients in Part B (to be presented in a future manuscript).Clinical trial registration:www.clinicaltrials.gov, identifier NCT04673383; https://www.clinicaltrialsregister.eu, identifier 2020-000251-13; https://www.isrctn.com/, identifier ISRCTN63465876.</p

Brain serotonin release is reduced in patients with depression: a [¹¹C]Cimbi-36 Positron Emission Tomography study with a d-amphetamine challenge

Background: The serotonin hypothesis of depression proposes that diminished serotonergic (5-HT) neurotransmission is causal in the pathophysiology of the disorder. Although the hypothesis is over 50 years old, there is no firm in vivo evidence for diminished 5-HT neurotransmission. We recently demonstrated that the 5-HT2A receptor agonist positron emission tomography (PET) radioligand [11C]Cimbi-36 is sensitive to increases in extracellular 5-HT induced by an acute d-amphetamine challenge. Here we applied [11C]Cimbi-36 PET to compare brain 5-HT release capacity in patients experiencing a major depressive episode (MDE) to that of healthy control subjects (HCs) without depression. Methods: Seventeen antidepressant-free patients with MDE (3 female/14 male, mean age 44 ± 13 years, Hamilton Depression Rating Scale score 21 ± 4 [range 16–30]) and 20 HCs (3 female/17 male, mean age 32 ± 9 years) underwent 90-minute dynamic [11C]Cimbi-36 PET before and 3 hours after a 0.5-mg/kg oral dose of d-amphetamine. Frontal cortex (main region of interest) 5-HT2A receptor nondisplaceable binding was calculated from kinetic analysis using the multilinear analysis-1 approach with the cerebellum as the reference region. Results: Following d-amphetamine administration, frontal nondisplaceable binding potential (BPND) was significantly reduced in the HC group (1.04 ± 0.31 vs. 0.87 ± 0.24, p < .001) but not in the MDE group (0.97 ± 0.25 vs. 0.92 ± 0.22, not significant). ?BPND of the MDE group was significantly lower than that of the HC group (HC: 15% ± 14% vs. MDE: 6.5% ± 20%, p = .041). Conclusions: This first direct assessment of 5-HT release capacity in people with depression provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating reduced 5-HT release capacity in patients experiencing an MDE