Editor’s summary

The clinical use of serotonergic psychedelics is limited by their side effects. Younkin et al. generated a derivative (called VCU-1012) of the psychedelic quipazine with greater activity at the serotonin receptor subtype that mediates the clinically desirable effects (5-HT2AR) than at the serotonin receptor subtype responsible for the undesirable ones. Similar to quipazine, VCU-1012 exerted antidepressant and antianxiolytic effects in mice but without the gastrointestinal side effects of quipazine. Moreover, like other psychedelics, VCU-1012 increased dendritic spine density in the frontal cortex in a 5-HT2AR–dependent manner. Thus, VCU-1012 shows promise as a 5-HT2AR agonist with a more favorable side effect profile than those of typical psychedelics. —Wei Wong

Abstract

Psychedelics that target serotonin 2A receptors (5-HT2ARs) hold therapeutic promise for neuropsychiatric disorders but are often hindered by off-target actions. The 5-HT2AR agonist quipazine also activates 5-HT3R, which contributes to undesirable side effects. Here, we developed VCU-1012, a quipazine-based, structurally distinct 5-HT2AR agonist devoid of 5-HT3R activity. VCU-1012 was developed by applying a strategic chemical design that combined deconstruction to pinpoint the nitrogen atom critical for 5-HT2AR activation with structure-activity relationship studies to minimize 5-HT3R agonism. We showed that VCU-1012 modulated dendritic spine structural plasticity in the frontal cortex and produced antidepressant-like effects in mice through 5-HT2AR without activating 5-HT3R, thereby avoiding the gastrointestinal side effects of quipazine. In addition, our molecular modeling and mutant analysis suggested that VCU-1012 interacted in the canonical orthosteric binding pocket of 5-HT2AR. Together, these findings establish VCU-1012 as a potential therapeutic agent with reduced gastrointestinal impact, emphasize how differences in ligand-receptor interactions influence ligand positioning in the receptor binding pocket, and provide guidance for designing psychedelics with targeted therapeutic benefits.

Amongst the FLY series (including DFLY, hemi[D]FLY etc) there exists isoFLY and hemi-isoFLY. I found the quote below and wondered whether anyone has further leads/information about this isoFLY class?

Congratulation M. Traschel. I live in the same country and we studied at the same time but not in the same university. I wish I could have more time to get my molecule tested and probably published. There is another team that made isoFLY structures that are apparently more potent than simple FLY or butterFLY, it didn't appear in the book but I'm pretty sure they designed for Traschel's team, it has been published somewhere but I don't remember where. Structure is here NCCC1=C2COCC2=C(Br)C2=C1COC2 . This is the full 2C-B-isoFLY but I think the most active was hemi-isoFLY, don't remember whether it was the 2- or 5- isomer.

Significance

The premise of these studies was to develop and validate a therapeutic for opioid use disorder. Using an AI-based platform aimed at polypharmacy-focused drug discovery, two compounds were synthesized and tested, GATC-021 and GATC-1021. We found that GATC-1021, which targets the 5-HT2A and 5-HT6 receptors,, was highly selective in attenuating fentanyl self-administration in male and female rats, with retained effectiveness following repeated dosing. Following GATC-1021 treatment, an increase in the percentage of thin dendritic spines in the hippocampus and changes in gene expression pathways involved in neuroplasticity in the prefrontal cortex were evidenced. Taken together, these findings provide a foundation to support the further clinical development of GATC-1021 as a potential treatment for individuals suffering from opioid use disorder.

Abstract

The opioid epidemic has led to a devastating loss of life nationwide. Of those dependent on opioids, many individuals desire to quit or reduce use, but their efforts are often unsuccessful given the powerful reinforcing properties associated with opioid drugs, including fentanyl. Here, we developed a therapeutic drug based on an AI-based platform, which was rationally designed to identify markers of dysregulation from human drug user postmortem brain tissue. Two top candidate compounds, GATC-021 and GATC-1021, were synthesized and validated with in vitro screening for target specificity. Thereafter, the drug candidates were examined for their effectiveness in modulating opioid reinforcement and intake. GATC-1021 emerged as the most efficacious compound as it significantly decreased fentanyl intake in both male and female rats, without any notable side effects. GATC-1021 was further found to modulate gene expression patterns in addiction-relevant brain regions following fentanyl-induced alterations. These findings validate GATC’s AI-based platform with its polypharmacy-focused drug development approach and further support the clinical potential of GATC-1021 as a promising therapeutic for those suffering from opioid use disorder.

Very cool, comprehensive in vitro screening coming out of the Javier Gonzalez Maeso lab :))

Abstract:

Serotonergic psychedelics have attracted considerable interest as promising therapeutic agents. However, the molecular mechanisms linking their acute hallucinogenic-like effects to longer-lasting neuroplastic responses remain incompletely understood, partly because of the scarcity of native neural models suitable for mechanistic studies. Here, we developed a neural stem cell-derived in vitro model capable of differentiating into neuronal and glial lineages and, after characterization, used it to investigate the molecular pharmacology of serotonergic psychedelics. A panel comprising tryptamines, phenethylamines and ergolines, including psychedelic compounds and selected non-psychedelic analogues, was evaluated alongside ketamine and TrkB agonists. Endpoints included dendritogenesis, synaptogenesis, immediate-early gene induction, BDNF expression and lactate production. TrkB silencing abolished dendritogenic responses to serotonergic psychedelics, ketamine and TrkB agonists, whereas 5-HT2A receptor silencing selectively impaired serotonergic psychedelic-induced plasticity and altered TrkB-dependent responses. Most serotonergic compounds also increased synaptogenesis and induced c-Fos and Egr-2 expression, although ligand-specific differences were evident, particularly for psilocin and the phenethylamines DOI and Ariadne. Uncoupling of Gq/11 or Gi/o protein-dependent signalling differentially modified neuroplastic and transcriptional responses, indicating a ligand and endpoint dependent contribution of both pathways. Serotonergic psychedelics further induced a 5-HT2A receptor dependent lactate response that was generally sensitive to disruption of either Gq/11 or Gi/o protein coupling. Taken together, these findings support a model in which serotonergic psychedelics recruit an integrated 5-HT2A–TrkB signalling network with distinct structural, transcriptional and metabolic outputs, and establish this neural stem cell-derived system as a valuable platform for screening and dissecting the signalling basis of psychedelic action.

The experimental 5-HT2AR structures have identified a hydrophobic tunnel lateral to the orthosteric site, situated in between the transmembrane helices 4 and 5. Here, we have examined this tunnel and its implications for 5-HT2AR agonist pharmacology. The tunnel characteristics and the key roles of Phe2345x39 and Gly2385x43 were delineated by molecular modeling and the synthesis and functional characterization of ten phenethylamine analogs. Molecular modeling, structure-activity relationship determination, and mutagenesis experiments demonstrate that the agonist potencies at the 5-HT2AR exhibited by analogs with 4-substituents with at least four heavy atoms are rooted in their ability to protrude into and form interactions within this tunnel. Thus, these findings provide new insights into the molecular basis for phenethylamine-induced 5-HT2AR activation and identify this tunnel, for the first time, as a druggable region to employ in designing potent 5-HT2AR agonists.

4-substituted 2,6-dimethoxyphenethylamines and the corresponding amphetamines (so-called pseudo [Ψ] derivatives) are a hitherto mostly unexplored group of psychedelics. Still, preliminary investigations indicate that these derivatives are promising and potent psychedelics in humans. In this study, we examined the monoamine receptor and transporter interaction properties of several 4-alkyloxy-2,6-dimethoxyphenethylamines and amphetamines with varying structural modifications at the 4-alkyloxy position and compared them to structural analogs with 3,4,5- and 2,4,5-substitution patterns.

The extracellular loop 2 (ECL2) of the serotonin 5-HT₂A receptor is a key determinant of ligand selectivity, yet the stereochemical requirements for ECL2 engagement by non-ergoline ligands remain unknown. Using CB-Dock2, we docked both enantiomers of α-methyl, α-ethyl, and α,α-dimethyl NBOH derivatives against two 5-HT₂A conformations — LSD-bound (PDB 6WGT) and 25CN-NBOH-bound Gq-coupled (PDB 6WHA)... Parent 2C-x, DOx compounds, unsubstituted NBOHs, mescaline, and LSD were docked as comparators. ...

Enantiomer-specific docking revealed a stereospecific ECL2 anchor site defined by LEU228, LEU229, PHE234, and VAL235. The anchor exhibits substituent-dependent enantiomer preference: (S) for 4-methyl, 4-cyano, and 4-ethyl compounds, (R) for α-ethyl compounds, and non-selective for 4-halogens. The (S)-enantiomer preference represents an inversion of the classical DOx (R)-preference.

Comparator docking demonstrated that neither α-methylation alone (DOE: -6.8) nor the N-benzyloxy group alone (25E-NBOH: -8.4) engages the anchor with high efficiency — the two modifications function cooperatively. Two compounds achieved focused anchor engagement: (S)-MaM (-9.6) and (R)-EaM (-9.4), with (R)-EaM making an additional aromatic contact at TRP141. (S)-CNaM achieved -10.1 — the highest score after LSD (-10.8) — with a -5.2 shift on 6WHA, exceeding LSD's conformational dependence (-4.5). Normalized selectivity analysis (all compounds scaled to a common 5-HT₂A reference of -10.0) with liabilities (5-HT₂B, α₁A, 5-HT₂C) separated from modulators (D₂, 5-HT₁A) revealed that α-substituted NBOH leads occupy the top rank in all three liability categories: (S)-CNaM for 5-HT₂B (-6.4), (S)-EaE for α₁A (-5.8), and (R)-FaM for 5-HT₂C (-7.1). LSD did not rank first in any liability category. Analysis of enantiomer pairs revealed a consistent S/R pattern: (S)-enantiomers tended toward higher 5-HT₂A affinity and cleaner adrenergic profiles, while (R)-enantiomers tended toward lower 5-HT₂C and D₂ activity. A predictive enantiomer preference rule emerged: when 4- and α-substituents are matched in size, (S) is preferred; when mismatched, (R) is preferred. Complete docking data are provided in master tables. These findings establish ECL2 stereochemistry as a tunable parameter in 5-HT₂A ligand design, demonstrate a cooperative allosteric mechanism, and identify specific leucine residues for experimental validation.

Due to the lack of pharmacological profiling, this study aimed to determine the potencies and structure-activity relationships (SARs) of recently emerged stimulants. 

Experimental Approach.

Employing in vitro human transporter inhibition assay and AequoScreen® 5HT2A receptor activity assay, potency, transporter selectivity, DAT/SERT, DAT/NET, and NET/SERT ratios, and group-wide structure-activity relationships of 58 substances were investigated. 

ISI and SCI scores improved significantly (both p < .001). Actigraphy confirmed longer total sleep time, higher sleep efficiency, and shorter sleep onset latency; after correction, ISI/SCI improvement and longer total sleep time remained significant. Clinically, 62.5% achieved meaningful improvement (≥7-point ISI reduction), 25% partial-to-minimal, and 12.5% no change or worsening; nearly two-thirds reached non-clinical insomnia levels. CPT-3 revealed enhanced sustained attention and response consistency, with further gains in selective attention and reduced impulsivity among responders. BAARS-IV showed overall improvement, with the sluggish cognitive tempo subscale reaching significance. Mood and anxiety improved, and the SDQ appetite/weight subscale decreased significantly even after correction, suggesting reduced perceived appetite or weight. Daridorexant was well tolerated; two participants reported daytime sleepiness or sedation, and one discontinued due to persistent sedation.

The serotonin 2C receptor is a G protein-coupled receptor implicated in multiple physiological and psychological processes and has been investigated as a therapeutic target for neuropsychiatric conditions such as obesity, drug abuse, and depression. With renewed interest in serotonergic psychedelics for treating depression, 5-HT2C may contribute to psychedelic-induced therapeutic effects. Despite earlier evidence of 5-HT2C G protein coupling promiscuity, the full signaling landscape remains incompletely characterized

Here, we provide a comprehensive analysis of 5-HT2C signaling, confirming and building upon previous findings that the receptor engages Gi/o/z and G12/13 proteins in addition to its primary Gq/11 pathway, and that it preferentially recruits β-arrestin2 over β-arrestin1. We also show that increased RNA editing of the receptor attenuates signaling across all G protein pathways, particularly for G12/13, while preserving β-arrestin recruitment.

Profiling of both 5-HT2C-selective and psychedelic ligands reveals diverse signaling profiles, with serotonergic psychedelics such as LSD and psilocin exhibiting a striking Gq/11 bias due to minimal secondary G protein activation. Altogether, this work provides a foundation for incorporating a broader view of 5-HT2C signaling modalities into future investigations of 5-HT2C drug development efforts.

We have confirmed the key role of 5-HT2A in the induction of HTR by 5-HTP and psilocybin, have demonstrated the effect of a 5-HT1A agonist to attenuate HTR and a bimodal contribution of 5-HT2C as well as a role of TAAR1 in modulating HTR induced by 5-HTP. 

These findings showed that while 5-HT2A is the main initiator of HTR, 5-HT2C also has a distinct property that renders it effective in inducing HTR in male mice.

Clausenamide is a plasticity-promoting natural product isolated from the leaves of Clausena lansium, an evergreen native to Southeast Asia and southern China. Herein, we report an efficient synthesis of this compound by a one-pot, three-component assembly of three of the four contiguous stereogenic centers. This method enabled efficient access to six stereoisomers and one analog, which were evaluated for their ability to induce synaptogenesis in primary cortical cultures using high-content imaging.

We observed a range of activities for clausenamide stereoisomers, but in general, the postsynaptic effects of the active compounds were greater than their presynaptic effects. Of the stereoisomers tested, (−)-cis-clausenamide exhibited the highest level of cortical synaptogenesis, with this effect likely being dependent on its ability to act as a 5-HT2AR partial agonist.

Activation of CB1 receptors by agonists induces analgesia but also induces cognitive impairment through the heteromer formed between CB1 and 5HT2A. This side effect poses a serious drawback in the therapeutic use of cannabis for pain alleviation. Peptides designed from the transmembrane helices of CB1R, which are predicted to bind 5HT2AR and alter the stability of the CB1R-5HT2AR heteromer, have been shown to avert CB1R agonist-induced cognitive impairment while preserving analgesia.

Using these peptides as templates, we have now designed nonpeptidic small molecules that prevent CB1R-5HT2AR heteromerization in bimolecular fluorescence complementation assays and the heteromerization-dependent allosteric modulations in cell signaling experiments. These results provide proof-of-principle for the design of optimized ligand-based disruptors of the CB1R-5HT2AR heteromer, opening new perspectives for in vivo studies.

Serotonin (5-HT) plays an important role in shaping brain network dynamics by regulating excitatory synaptic function and neuronal excitability. However, much less is known about how 5-HT tunes synaptic inhibition. Here, we demonstrate that transient 5-HT signaling persistently suppresses GABAergic synapses onto layer 2/3 pyramidal neurons in the medial prefrontal cortex (mPFC). Moreover, we found that 5-HT1A and 5-HT2A receptors differentially contribute to 5-HT regulation of synaptic inhibition, possibly by acting at distinct GABAergic cell subpopulations.

Importantly, 5-HT2A receptor activation triggers retrograde endocannabinoid signaling to reduce GABA release selectively at synapses formed by somatostatin (SST+)- but not parvalbumin (PV+)-positive GABAergic interneurons. Altogether, our results highlight the diverse molecular and cell-type-specific mechanisms by which 5-HT signaling modulates inhibitory circuits to shape cortical function. 

Endocannabinoids are lipid retrograde messengers that can be released by postsynaptic depolarization and/or activation of certain metabotropic receptors. We review a recent report that activation of metabotropic 5-HT2 receptors by endogenous serotonin induces the release of endocannabinoids in the olivary nucleus and suppresses glutamatergic input through a presynaptic action. This serotonin–endocannabinoid interaction has implications in the pathophysiology of pain and mental illness and raises the possibility that drugs targeting the 5-HT2 receptor may act by modulating endocannabinoid release.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders.

Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy structures of 5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour.

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-HT1A agonists. We show that a 5-HT1A-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-HT1A-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.

Summary:
Caffeine consumption 30-60mg it’s prior to Sabroxy is the best way to capture its stimulatory effects (Dopamine transport inhibition and KOR antagonism) at the expense of its pro neurogenesis and BDNF. If the goal is to increase focus and attention we want to avoid the A2A agonist properties, preloading with a competitive antagonist at A2A (like caffeine) prevents this A2A agonism by blocking the orthosteric site on the receptor. This increase arousal by preventing inhibition of key nuclei involved in the release of norepinephrine, acetylcholine, serotonin, and histamine all of which collectively contribute to concentration and focus by maintaining the conditions for wakefulness.

Sabroxy® is a premium standardized extract derived from the bark of Oroxylum indicum, delivering exactly 10% oroxylin-A (ND product overview)

In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor.

Citation:
Yoon, S.Y., dela Peña, I., Kim, S.M. et al. Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro. Arch. Pharm. Res. 36, 134–140 (2013). https://doi.org/10.1007/s12272-013-0009-6

Overall, oroxylin A might regulate BDNF production in cortical neuron through A2A receptor stimulation
[…A2A agonist] which promotes cellular survival, synapse formation and neurite extension

Citation:
January 2012Biomolecules and Therapeutics 20(1):27-35
DOI:10.4062/biomolther.2012.20.1.027

A2A receptors are inhibitory G of i/o leading to decreased activity.

A2A receptors are expressed in key brain regions associated with arousal (energy and wakefulness NOT sexual arousal) and attention, specially the Tuberomammilary nucleus (TMN) responsible for histamine release a key neurotransmitter associated with consciousness/wakefulness and is generally precognitive, locus coeruleus (LC) the primary source of Norepinephrine (NE) in the brain which is probably equally if not more important for arousal and sustained attention and is one of the three foundational neurotransmitters/neuromodulatory involved in sustained attention and concentration, as well as the Dorsal Raphe Nucleus (DRG) the primary source of serotonin/5-hydroxytryptamine (5-HT) Brain also invoked in modulating the excitability and sensitivity of neuronal circuits throughout the brain.

Lastly, we have the Lateral Dorsal Tegmental Nucleus (LDT) and the pedunctopontine tegmental nucleus (PPT) these are big sources of acetylcholine.

NE+DA+ACh are the core neurotransmitter needed for focus and attention. Sabroxy blocking this receptor leads to reduced levels of arousal

A lesser known fact is Baicalein is a KOR antagonist. Kappa opioid receptors function like brakes on the dopamine system so reliving this inhibition would increase DAergic activity

In the study, we found that the isolated compound baicalein (3) has shown the most potent and competitive antagonistic activity at 20 mg/kg dose in vivo experiments. The acute dose of 3 (20 mg/kg) and pan opioid receptor antagonist naloxone (20 mg/kg) block the morphine-induced antinociception and the paw withdrawal latency decreases up to 8.3 s and 9.6 s, respectively. The in silico studies also support our in vitro data that compound 3 binds with MOR and KOR.

Citation:
Singh, K., Yadav, A., Khan, S., Shukla, A., Alam, M., Verma, A. K., … Dev, K. (2025). Baicalein isolated from Oroxylum indicum acts as a potent µ- and κ-opioid receptor antagonist agent via the reversal of agonist-mediated cAMP inhibition. Natural Product Research, 39(23), 6837–6845. https://doi.org/10.1080/14786419.2024.2396452

DRI+KOR antagonism+GABA-A NAM work together to increase focus and now with the A2A agonism blocked you can fully harness the stimulatory benefits. I also like to take a cold shower with Sabroxy to promote NE+DA release and with the DRI effect they work synergistically.

Also, my guess is that the MOR antagonism may be partially responsible for the increase anxiety reported and if you’re actively taking opioids this may intervene with the analgesia due to reduced cAMP suppression from Baicalein.

The serotonin 1A receptors and serotonin transporter are important biological targets in the treatment of diseases of the central nervous system, especially for depression. In this study, new 3-(1H-indol-3zyl)pyrrolidine-2,5-dione derivatives linked with the 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole moiety were synthesised and evaluated for their affinity for 5-HT1A receptor and serotonin reuptake inhibition.

Selected compounds were then tested for their affinity for D2, 5-HT2A, 5-HT6 and 5-HT7 receptors, and also in-vitro metabolic stability assays in human microsomes. Finally, in vivo assays allowed us to evaluate the agonist–antagonist properties of pre- and postsynaptic 5-HT1A receptors. 3-(1-(4-(3-(5-methoxy-1H-indol-3-yl)-2,5-dioxopyrrolidin-1-yl)butyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-5-carbonitrile (4f) emerged as the most promising compound from the series, due to its favourable receptor binding profile (K:HT1A = 10.0 nM; K:SERT = 2.8 nM), good microsomal stability and 5-HT1A receptor agonistic activity.

In this study, we designed and synthesized novel 5-HT2A partial agonists based on the structures of the antipsychotic drug aripiprazole and our previously reported lead compound IHCH-7086. Two series of new compounds were synthesized, a number of which exhibited potent 5-HT2A partial agonist activity in G protein coupling and β-arrestin2 recruitment assays.

They "rediscovered" a desmethylene-type LSD analog (see 23m) similar to compound 11 from this patent.

This is a spicy meatball (but a fresh preprint so proceed with caution)

Coming from the Roth lab, is a challenge to decades of work coming from Javier Gonzalez Maeso's lab (oooh drama) - while there is still an established functional relationship between 5HT2A/mGlu2 - the Roth lab, using cutting edge technology, was unable to discern a physical interaction between the two in vitro/vivo. A good read for the mechanistic psychedelic enthusiast 🌝

Abstract:

is well established that activating the mGluR2 metabotropic glutamate receptor (mGluR2), which is the main presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological actions of LSD and other psychedelics. However, the mechanisms responsible for these actions are controversial. The two competing mechanistic hypotheses have been proposed to explain this phenomenon are: (1) direct actions mediated by mGluR2/5-HT2A heterodimers, and (2) inhibition of 5-HT2A-mediated excitation of pyramidal neurons via presynaptic inhibition of glutamate release by mGluR2 receptors. Consistent with prior reports, we show mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in these mice. We next employed multiple orthogonal in vivo and in vitro approaches to explore the potential for direct physical interactions between mGluR2 and 5-HT2A receptors. We next engineered mice to express mGluR2-mCherry-CT and 5-HT2A-eGFP-CT tagged receptors and found no evidence for receptor colocalization or oligomerization under basal or 5-HT2A agonist-exposed conditions in vitro or in vivo. Radioligand binding and kinetic analyses revealed no evidence for mGluR2-mediated modulation of 5-HT2A ligand binding in vitro or in vivo. Collectively, our findings support models in which mGluR2 signaling modulates the activity of Gq-coupled 5-HT2A receptors in layer V pyramidal neurons, rather than models positing the requirement of mGluR2/5-HT2A multimers.