⫸STICKY⫷ The N&PD Recent Journal ARTICLE Club

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On a side note, I am also curious about Sodium Acetate Tri-Hydrate as a catalyst instead of Sulfuric/ Phosphoric acid.
Some of them have appreciable affinities at other sites (mainly DAT and sigma receptors), a 10-fold selectivity isn't really considered very selective.
 

CFC

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My 18 year access to Uni journals will be coming to an end within the next year. It's going to kill me to not be able to just read whatever I fancy, but anyway if anyone lacking this luxury is itching to read a full paper they can't find elsewhere, please post a link and I'll see if we're subscribed.
 

Jonneh

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Interesting Nature paper on the mechanism of Ketamine's antidepressant effects:

NMDAR inhibition-independent antidepressant actions of ketamine metabolites

Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
To sum up briefly: the effectiveness of ketamine as an antidepressant stems not from its action as an antagonist of NMDA receptors, as was previously thought, but rather those of one of its metabolites (blocking the metabolic step blocked the beneficial effects of ketamine). The metabolite is non-psychoactive, and turns out to act on AMPA receptors (it activates them, and preventing their activation blocks the antidepressant effects). Quite a turn up for the books!
 

yoyoman

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I just started getting into it, used one of those links (thanks!) for the free journal downloads..

This is for MDPV and about the two isomers one causing side effects/psychosis the other causing stim effects is what it looks like on the surface.

I think its even more crazy with certain other compounds like 4-CL-PVP will make you see UFO's and aliens while you can fall asleep (atypical of stimulant psychosis.. the 4-cl doesn't feel stimulating)

I wonder if just the S isomer / dextro versions would be awesome stimulants with medical use.

http://onlinelibrary.wiley.com/doi/10.1002/chir.22423/full

article available free through those websites.
 

sekio

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A nontoxic pain killer designed by modeling of pathological receptor conformations

Indiscriminate activation of opioid receptors provides pain relief but also severe central and intestinal side effects. We hypothesized that exploiting pathological (rather than physiological) conformation dynamics of opioid receptor-ligand interactions might yield ligands without adverse actions. By computer simulations at low pH, a hallmark of injured tissue, we designed an agonist that, because of its low acid dissociation constant, selectively activates peripheral m-opioid receptors at the source of pain generation. Unlike the conventional opioid fentanyl, this agonist showed pH-sensitive binding, heterotrimeric guanine nucleotide–binding protein (G protein) subunit dissociation by fluorescence resonance energy transfer, and adenosine 3′,5′-monophosphate inhibition in vitro. It produced injury-restricted analgesia in rats with different types of inflammatory pain without exhibiting respiratory depression, sedation, constipation, or addiction potential.

http://science.sciencemag.org/content/355/6328/966

Another non-toxic, non-addictive, "perfect" opioid ... 8) maybe instead of fucking with random fent analogs people could make the one described in the paper?
 

sekio

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Enzymatic synthesis of psilocybin
http://onlinelibrary.wiley.com/doi/10.1002/anie.201705489/abstract

Abstract

Psilocybin is the psychotropic tryptamine-derived natural product of Psilocybe carpophores, the so-called "magic mushrooms". Although its structure has been known for 60 years, the enzymatic basis of its biosynthesis has remained obscure. We characterized four psilocybin biosynthesis enzymes. These include i) PsiD which represents a new class of fungal l-tryptophan decarboxylases, ii) PsiK, that catalyzes the phosphotransfer step, iii) the methyl transferase PsiM, catalyzing iterative N-methyltransfer as terminal biosynthetic step, and iv) PsiH, a monooxygenase. In a combined PsiD/PsiK/PsiM reaction, psilocybin was synthesized enzymatically in a step-economic route from 4-hydroxy-l-tryptophan. Given the renewed pharmaceutical interest in psilocybin, our results may lay the foundation for its biotechnological production.
 

sekio

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Stimulants don't effect people with ADD any differently than others
https://www.nature.com/articles/1301164

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating ‘normal’ individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well.
 

sekio

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Trapping of Syntaxin1a in Presynaptic Nanoclusters by a Clinically Relevant General Anesthetic
Adekunle T. Bademosi, James Steeves, Shanker Karunanithi, Oressia H. Zalucki, Rachel S. Gormal, Shu Liu, Elsa Lauwers, Patrik Verstreken, Victor Anggono, Frederic A. Meunier, Bruno van Swinderen
Propofol is the most commonly used general anesthetic in humans. Our understanding of its mechanism of action has focused on its capacity to potentiate inhibitory systems in the brain. However, it is unknown whether other neural mechanisms are involved in general anesthesia. Here, we demonstrate that the synaptic release machinery is also a target. Using single-particle tracking photoactivation localization microscopy, we show that clinically relevant concentrations of propofol and etomidate restrict syntaxin1A mobility on the plasma membrane, whereas non-anesthetic analogs produce the opposite effect and increase syntaxin1A mobility. Removing the interaction with the t-SNARE partner SNAP-25 abolishes propofol-induced syntaxin1A confinement, indicating that syntaxin1A and SNAP-25 together form an emergent drug target. Impaired syntaxin1A mobility and exocytosis under propofol are both rescued by co-expressing a truncated syntaxin1A construct that interacts with SNAP-25. Our results suggest that propofol interferes with a step in SNARE complex formation, resulting in non-functional syntaxin1A nanoclusters.

http://www.cell.com/cell-reports/fulltext/S2211-1247(17)31878-8
 

JacksinPA

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https://www.frontiersin.org/articles/10.3389/fpsyt.2017.00152/full
Novel Psychoactive Substances-Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs - Zurina Hassan1, Oliver G. Bosch2, Darshan Singh1, Suresh Narayanan3, B. Vicknasingam Kasinather1, Erich Seifritz2, Johannes Kornhuber4, Boris B. Quednow5 and Christian P. M?ller4*


A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug?s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine ('Kratom'), synthetic cannabinoids (e.g., 'Spice'), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
 
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LucidSDreamr

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Stimulants don't effect people with ADD any differently than others
https://www.nature.com/articles/1301164

Stimulants such as methylphenidate and amphetamine are currently the most common treatment for attention deficit hyperactivity disorder (ADHD). For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients, whereas stimulating ?€˜normal?€™ individuals and producing locomotor activation in rats. It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects. Furthermore, the seminal work of Kuczenski and Segal showed that low, oral doses of methylphenidate reduce locomotor activity in rats as well.

People love to say otherwise
 

sekio

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Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis
We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2.13 (95% credible interval [CrI] 1.89-2.41) for amitriptyline and 1.37 (1.16-1.63) for reboxetine. For acceptability, only agomelatine (OR 0.84, 95% CrI 0.72-0.97) and fluoxetine (0.88, 0.80-0.96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1.30, 1.01-1.68). When all trials were considered, differences in ORs between antidepressants ranged from 1.15 to 1.55 for efficacy and from 0.64 to 0.83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1.19-1.96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0.51-0.84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0.43-0.77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1.30-2.32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.

All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext

Very interesting.
 

Vickki1000

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The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Developmen

[FONT=.SF UI Text][FONT=.SFUIText]Thoughts? The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions[/FONT][/FONT]
[FONT=.SF UI Text][FONT=.SFUIText]http://www.cell.com/cell-reports/fulltext/S2211-1247(18)30189-X[/FONT][/FONT]
 
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Cotcha Yankinov

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I think alpha2delta and NMDAr upregulation aren't the end all be all of neuropathic pain but they're certainly important
 

Vickki1000

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I agree Gabapentin certainly not the end all of much of anything. This study was just released publicly and I thought the new MOA associated with NMDA/NMDAR was interesting. Thoughts?
 
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