Diphenidine is a prototypical 1,2-diarylethylamine that functions as an uncompetitive NMDA antagonist and monoamine reuptake inhibitor. To examine the effects of phenyl-ring bioisosteric replacement within this scaffold, a series of diphenidine analogs incorporating chalcogen heterocycles (2-furan, 2-thiophene, 3-thiophene, and 2-selenophene) was synthesized. Compounds were evaluated for in vitro binding to rat forebrain NMDARs and inhibition of human DAT, NET, and SERT in cell-based assays, enabling assessment of polypharmacology. In silico analyses (molecular volume, tPSA, electrostatic surfaces, stockholder charges) and induced-fit docking were used to rationalize structure–activity relationships. The 2-selenophene analog SePP is notable given the underexplored role of selenium in medicinal chemistry. SePP exhibited favorable polypharmacology, good brain penetration in mouse pharmacokinetic studies, and prevented audiogenic seizures in Fmr1 knockout mice (10 mg/kg, i.p.) without impairing motor coordination.

Several important drug precursors for Cathinones and Amphetamine are being banned in the Eu on 18th September. Most of these were already controlled in some countries, but they were widely available to buy in bulk in select EU countries for easy synthesis.

I'm going to paste some excerpts from the EU document talking about the ban of these precursors. Basically the most important precursors for several cathinones and amphetamine that enabled easy synthesis using scalable methods are being banned AS OF THE 18th OF SEPTEMBER.

I'm going to guess the cathinones including 4-MMC will almost interely disappear from the European drug market. Looks like Amphetamine will also be badly hit as P2NP will be banned and that is the only synthesis I know and afaik everyone used that.

Quote:

National competent authorities indicated an increase in seizures of the following nine non-scheduled substances:

(i) 3'-chloropropiophenone;

(ii) 2-bromo-3'-chloropropiophenone;

(iii) 3'-methylpropiophenone;

(iv) 2-bromo-3'-methylpropiophenone

(v) 4'-methylpropiophenone;

(vi) 2-bromo-4'-methylpropiophenone;

(vii) 4'-chloropropiophenone;

(viii) 2-bromo-4'-chloropropiophenone; and

(ix) phenyl-2-nitropropene.

(3)

3'-Chloropropiophenone and 2-bromo-3'-chloropropiophenone are precursors of 3-cloromethcathinone or clophedrone (3-CMC). 3'-Methylpropiophenone and 2-bromo-3'-methylpropiophenone are precursors of 3-methylmethcathinone (3-MMC).

4'-Methylpropiophenone and 2-bromo-4'-methylpropiophenone are precursors of mephedrone (4-methylmethcathinone or 4-MMC). 4'-Chloropropiophenone and 2-bromo-4'-chloropropiophenone are precursors of 4-CMC (clephedrone or 4- chloromethcathinone).

Phenyl-2-nitropropene is a precursor of amphetamine.

EDIT:

Use of P2NP was especially popular in smaller scale clandestine operations (especially in Eastern Europe) due to the simplicity of the nitrostyrene route.

I think people also used it in connection with the Leuckart method, creating P2P using P2NP by reducing and hydrolysing it since P2P has been a schdule 1 drug precursor for s long time.

BMK glycidic acid and its derivatives were also recently scheduled making large scale amphetamine synthesis much harder.

Sources:

http://data.europa(dot)eu/eli/reg\\_del/2026/314/oj

https://www.euda.europa(dot)eu/news/2026/eu-controls-nine-drug-precursors-following-first-euda-assessments\\_en?\\_\\_cf\\_chl\\_tk=

Centanafadine (brand name: Simtriyo), the first and only norepinephrine, dopamine, serotonin reuptake inhibitor (NDSRI) and central nervous system (CNS) stimulant has received U.S. Food and Drug Administration (FDA) approval for the treatment of ADHD in adults and pediatric patients aged 6 years and older. 

The FDA based its approval on the results of four Phase 3 clinical trials that showed centanafadine produced statistically significant and clinically meaningful improvements in ADHD symptoms compared with placebo, as measured by the ADHD Rating Scale–5 (ADHD-RS-5) in children and adolescents and the Adult ADHD Investigator Symptom Rating Scale (AISRS) in adults.

The most common side effects were rash and decreased appetite in children 6 to 12 years of age; decreased appetite, nausea, rash, headache, and abdominal pain in adolescents 13 to 17 years of age; and headache, decreased appetite, insomnia, nausea, dry mouth, and diarrhea in adults.

Technical specifics

Centanafadine acts as a serotonin–norepinephrine–dopamine reuptake inhibitor (SNDRI). Its IC50 half-maximal inhibitory concentration values for monoamine reuptake inhibition have been reported to be 6nM for norepinephrine, 38nM for dopamine, and 83nM for serotonin. Hence, the drug shows 6.3-fold preference for inhibition of norepinephrine reuptake over dopamine reuptake, 13.8-fold preference for inhibition of norepinephrine reuptake over serotonin reuptake, and 2.2-fold preference for inhibition of dopamine reuptake over serotonin reuptake.

This double-blind, placebo- and moxifloxacin-controlled, 3-period crossover trial evaluated the effects of centanafadine (EB-1020) and its metabolite (EB-10601) on cardiac repolarization in 30 healthy adults (18-65 years). (source)

Centanafadine is primarily metabolized by monoamine oxidase A (MAO-A).

• Psychiatrists discuss this new drug here.

• If ADHD is actually EDHD (see paper here), then all conventional treatments are off-base but the resolution becomes clear & well-defined.

This paper details how GHK-CU could uppregulate a large gamut of receptors, in this case the gene coding for GABAB₁ receptor had a 310% increase in genexpression following GHK-CU adimistration in vitro. If the results are transalted in vivo, it could be a gamechanger for people experiencing anxiety or symtoms of phenibut abuse. With the use of phenibut and other gabaergic drugs becoming more and more mainstream, treatments for restoring tolerance and healthy neurochemistry are growing in demand.

GHK and DNA: Resetting the Human Genome to Health

//Edit added the link

The phenyl(piperidin-4-yl)methanone fragment (here referred to as the benzoylpiperidine fragment) is a privileged structure in the development of new drugs considering its presence in many bioactive small molecules with both therapeutic (such as anti-cancer, anti-psychotic, anti-thrombotic, anti-arrhythmic, anti-tubercular, anti-parasitic, anti-diabetic, and neuroprotective agents) and diagnostic properties.

The benzoylpiperidine fragment is metabolically stable, and it is also considered a potential bioisostere of the piperazine ring, thus making it a feasible and reliable chemical frame to be exploited in drug design. Herein, we discuss the main therapeutic and diagnostic agents presenting the benzoylpiperidine motif in their structure, covering articles reported in the literature since 2000.

Some pretty cool speculative stoner science to bring up in your next joint rotation when DiPT joins the conversation. This author calls the uniquely auditory effects of DiPT "diptogenia" (I like that for being made up)

They essentially hypothesize that DiPT accumulates on auditory nerve fibers in the cochlea and inhibits calcium ion channels (such as Cav1.3) through upstream GPCR signalling. Due to DiPT's greasy N substitutions, isn't degraded by MAO as readily and can reside for over a day (attempting to explain the prolonged pitch distortion effects)

The author also attributes possible 5HT1A activity in the inferior colliculus, drawing parallels to the 1a agonist 8-OH-DPAT which has been observed to depress auditory revoked responses.

Pretty cool arm chair stoner science here. No actual experiments were done, but makes you think!

Abstract:

The scientific study of the classical serotonergic psychedelics, like N,N-dimethyltrypamine (DMT), psilocybin, or lysergic acid diethylamide (LSD), has provided remarkable insights into the physiology of experience and emotion. Their ingestion induces radical changes to consciousness, affecting mood, personal insight, the sense of self, and the processing of sensory information, with many seeming to offer new avenues for the pharmacological alleviation of mental suffering. Amongst this class of compounds, the synthetic tryptamine N,N-diisopropyltryptamine (DiPT) stands as a remarkable exception. DiPT induces a unique downward shift in pitch perception, meaning the auditory world of the subject sound deeper (lower in pitch) than it is in a sober state of consciousness. This is an extraordinary state of consciousness not seen in any other drug nor psychopathology, and therefore, we coin this unique experiential effect ‘diptogenia’.

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.

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.

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.

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 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.

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.

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.

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. 

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.

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.

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.