While watching this old VICE episode I saw an ergoline alkaloid I'd never heard of. So alongside bromo DMT there are 2-bromo ergolines produced by an ascidian sea squirt. The 2nd picture shows the classic ergoline alkaloids.
>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.
It's commonly believed that mescaline is deaminated by MAO (Shulgin used an MAO-B inhibitor) but it's more likely to be enzyme called SSAO.
>Semicarbazide-Sensitive Amine Oxidase (SSAO) is an enzyme that catalyzes the oxidative conversion of primary amines to their corresponding aldehydes.
The SSAO inhibitor called "semicarbazide" completely prevented mescaline deamination as outlined in this quote which assessed all possible ring-methoxylated phenethylamines:
>All of the remaining ring-methoxylated phenethylamines are deaminated at appreciable rates, with some variation in rate with structure. Mescaline, however, is unique in that its deamination is completely inhibited by 0.005 / semicarbazide. Semicarbazide does not inhibit the deamination of any of those ring-methoxylated phenethylamines which do undergo deamination, and in this respect these amines behave in the same manner as tyramine or unsubstituted phenethylamine when they are presented as substrates for amine oxidase systems. (source)
You might assume that an SSAO inhibitor would potentiate mescaline but it might not be so simple. imo mescaline is handled very uniquely compared to other phenethylamines. Its activity depends on it being metabolised implying SSAO is the key first step to formation of active metabolites (which may be quaternary metabolites).
Blocking SSAO would theoretically weaken the dose. SSAO produces "mescaline aldehyde" which is to be protected and kept intact. ALDH oxidises aldehydes (it turns acetaldehyde into acetic acid) so an ALDHI is ideal for mescaline as reported here:
Potential ALDHIs include:
Add-on ALDHIs:
Since the idea is to reduce ALDH, avoiding things which induce it also helps. The most common strongest inducer is sulforaphane from cruciferous vegetables.
Here's a relevant quote from a 2022 study on 3,4,5 type phenethylamines: >However, different downstream signaling cascades, biased agonism, and other pharmacological targets may contribute to the subjective effects. Mescaline binds and activates the 5-HT2A receptor as partial agonist with low potency in vitro. Nevertheless, in vivo, it induces intense and long lasting psychedelic effects if applied at high doses. This suggests that low affinity binding to the receptor does not exclude marked psychoactivity in vivo...
>However, for 3,4,5-substituted derivatives additional pharmacological interactions or targets may significantly contribute to the overall psychedelic effects observed in humans. (source)
This earlier post has more technical details on the ALDH method, see ½ way down.
Context:
(not me, just sharing)
>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.
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.
>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.
Thank you!
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.
>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.
>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.
Thank you!
>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.
Thank you
How would you name this? That's a dihydropyran ring so DHP seems appropriate.
In the conventional world of ADHD, people believe in their medication. Commonly that's a form of amphetamine which they're prescribed and take daily for years. Side-effects? Maybe...
Some recent posts from an ADHD group...
>Amphetamine causing significant deterioration yet the user wants to continue, and doesn't understand what's happening.
>A chronic amphetamine user explains why taking a 2-day break is a "bad idea".
>— "I’m on 60 mg. When I’m lying down my heart beat skips a beat every few seconds. I don’t think I had this before. What do I do"
>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.
