Ketamine salts solubility

[Cortexiphan]

DARK Classics in Chemical Neuroscience: NBOMes
Authors: Christian B. M. Poulie, Anders A. Jensen, Adam L. Halberstadt, Jesper L. Kristensen*
ACS Chem. Neurosci. 2019,
Publication Date:October 28, 2019
https://doi.org/10.1021/acschemneuro.9b00528

N-Benzylphenethylamines, commonly known as NBOMes, are synthetic psychedelic compounds derived from the phenethylamine class of psychedelics (2C-X compounds), which originally have been derived from the naturally occurring alkaloid mescaline. Analogously to their parent compounds and other classical psychedelics, such as psilocybin and lysergic acid diethylamide (LSD), NBOMes are believed to exert their main pharmacological effects through activation of serotonin 2A (5-HT2A) receptors. Since their introduction as New Psychoactive Substances (NPSs) in 2010, NBOMes have been widely used for recreational purposes; this has resulted in numerous cases of acute toxicity, sometimes with lethal outcomes, leading to the classification of several NBOMes as Schedule I substances in 2013. However, in addition to their recreational use, the NBOMe class has yielded several important biochemical tools, including [11C]Cimbi-36, which is now being used in positron emission tomography (PET) studies of the 5-HT2A and 5-HT2C receptors in the mammalian brain, and 25CN-NBOH, one of the most selective 5-HT2A receptor agonists developed to date. In this Review, the history, chemistry, structure–activity relationships, ADME (absorption, distribution, metabolism, and excretion) properties, and safety profiles of NBOMes will be outlined and discussed.

 

[polymath]

Examining the short-term anxiolytic and antidepressant effect of Floatation-REST
Authors: Justin S. Feinstein, Sahib S. Khalsa, Hung-wen Yeh, Colleen Wohlrab, Murray B. Stein, Martin P. Paulus
PLoS One. 2018; 13(2): e0190292.
doi: 10.1371/journal.pone.0190292

Abstract
Floatation-REST (Reduced Environmental Stimulation Therapy) reduces sensory input to the nervous system through the act of floating supine in a pool of water saturated with Epsom salt. The float experience is calibrated so that sensory signals from visual, auditory, olfactory, gustatory, thermal, tactile, vestibular, gravitational and proprioceptive channels are minimized, as is most movement and speech. This open-label study aimed to examine whether Floatation-REST would attenuate symptoms of anxiety, stress, and depression in a clinical sample. Fifty participants were recruited across a spectrum of anxiety and stress-related disorders (posttraumatic stress, generalized anxiety, panic, agoraphobia, and social anxiety), most (n = 46) with comorbid unipolar depression. Measures of self-reported affect were collected immediately before and after a 1-hour float session, with the primary outcome measure being the pre- to post-float change score on the Spielberger State Anxiety Inventory. Irrespective of diagnosis, Floatation-REST substantially reduced state anxiety (estimated Cohen’s d > 2). Moreover, participants reported significant reductions in stress, muscle tension, pain, depression and negative affect, accompanied by a significant improvement in mood characterized by increases in serenity, relaxation, happiness and overall well-being (p < .0001 for all variables). In reference to a group of 30 non-anxious participants, the effects were found to be more robust in the anxious sample and approaching non-anxious levels during the post-float period. Further analysis revealed that the most severely anxious participants reported the largest effects. Overall, the procedure was well-tolerated, with no major safety concerns stemming from this single session. The findings from this initial study need to be replicated in larger controlled trials, but suggest that Floatation-REST may be a promising technique for transiently reducing the suffering in those with anxiety and depression.

 

[sekio]

Mystery of why magic mushrooms go blue solved
By Katrina Krämer
10 December 2019

Mystery of why magic mushrooms go blue solved

Chemists reveal colourful indigo-like polymers that turn psychotropic mushrooms blue when cut

www.chemistryworld.com

Why do magic mushrooms turn blue when they are cut? Chemists have now unravelled this decade-old mystery, in the process revealing that the dark blue pigments at the centre of the mystery are similar to indigo, the dye used to produce blue jeans.

Journal article: Injury‐Triggered Blueing Reactions of Psilocybe “Magic” Mushrooms
Claudius Lenz, Dr. Jonas Wick, Dr. Daniel Braga, Dr. María García‐Altares,Dr. Gerald Lackner, Prof. Dr. Christian Hertweck, Dr. Markus Gressler, Prof. Dr. Dirk Hoffmeister

Upon injury, psychotropic psilocybin‐producing mushrooms instantly develop an intense blue color, the chemical basis and mode of formation of which has remained elusive. We report two enzymes from Psilocybe cubensis that carry out a two‐step cascade to prepare psilocybin for oxidative oligomerization that leads to blue products. The phosphatase PsiP removes the 4‐O‐phosphate group to yield psilocin, while PsiL oxidizes its 4‐hydroxy group. The PsiL reaction was monitored by in situ 13C NMR spectroscopy, which indicated that oxidative coupling of psilocyl residues occurs primarily via C‐5. MS and IR spectroscopy indicated the formation of a heterogeneous mixture of preferentially psilocyl 3‐ to 13‐mers and suggest multiple oligomerization routes, depending on oxidative power and substrate concentration. The results also imply that phosphate ester of psilocybin serves a reversible protective function.

https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201910175

 

[checktest]

Biological psychiatry has a whole free issue on the "Neurobiology of the Opioid Epidemic"

https://www.biologicalpsychiatryjournal.com/issue/S0006-3223(18)X0025-0

Example article:

Molecular Basis of Opioid Action: From Structures to New Leads
Author: Manglik, Aashish
2020. Biological Psychiatry, Volume 87, Issue 1, 6 - 14.


Since the isolation of morphine from the opium poppy over 200 years ago, the molecular basis of opioid action has remained the subject of intense inquiry. The identification of specific receptors responsible for opioid function and the discovery of many chemically diverse molecules with unique opioid-like efficacies have provided glimpses into the molecular logic of opioid action. Recent revolutions in the structural biology of transmembrane proteins have, for the first time, yielded high-resolution views into the 3-dimensional shapes of all 4 opioid receptors. These studies have begun to decode the chemical logic that enables opioids to specifically bind and activate their receptor targets. A combination of spectroscopic experiments and computational simulations has provided a view into the molecular movements of the opioid receptors, which itself gives rise to the complex opioid pharmacology observed at the cellular and behavioral levels. Further diversity in opioid receptor structure is driven by both genetic variation and receptor oligomerization. These insights have enabled computational drug discovery efforts, with some evidence of success in the design of completely novel opioids with unique efficacies. The combined progress over the past few years provides hope for new, efficacious opioids devoid of the side effects that have made them the scourge of humanity for millennia.

Doi: https://doi.org/10.1016/j.biopsych.2019.08.028

 

[polymath]

Polo Sara, Díaz Andrés Felipe, Gallardo Núria, Leánez Sergi, Balboni Gianfranco, Pol Olga, "Treatment With the Delta Opioid Agonist UFP-512 Alleviates Chronic Inflammatory and Neuropathic Pain: Mechanisms Implicated", Frontiers in Pharmacology, Volume 10, 2019, page 283.

Frontiers | Treatment With the Delta Opioid Agonist UFP-512 Alleviates Chronic Inflammatory and Neuropathic Pain: Mechanisms Implicated

We investigated whether administration of the δ-opioid receptor (DOR) agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), which also activates nuclear factor er...

www.frontiersin.org

We investigated whether administration of the δ-opioid receptor (DOR) agonist H-Dmt-Tic-NH-CH(CH2-COOH)-Bid (UFP-512), which also activates nuclear factor erythroid 2-related factor 2 (Nrf2), alleviated chronic inflammatory and/or neuropathic pain and inhibited the depressive-like behaviors associated with persistent neuropathic pain. The possible mechanisms implicated were also assessed. We evaluated the following effects in male C57BL/6J mice with inflammatory pain induced by complete Freund’s adjuvant or neuropathic pain caused by the chronic constriction of sciatic nerve: (1) the antinociceptive effects of UFP-512; (2) the effects of UFP-512 on the expression of Nrf2, heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1, phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), inducible nitric oxide synthase, DOR, and mitogen-activated protein kinases (MAPK) in the spinal cord of animals with inflammatory or neuropathic pain; (3) the antinociceptive effects of the coadministration of UFP-512 with the Nrf2 activator sulforaphane (SFN); and (4) the antidepressant effects of UFP-512 in animals with depressive-like behaviors associated with neuropathic pain. Our results demonstrated that the intraperitoneal administration of UFP-512 inhibited chronic inflammatory and neuropathic pain and reduced the depressive-like behaviors associated with persistent neuropathic pain. The antiallodynic effects of UFP-512 were significantly augmented when it was coadministered with SFN in both types of chronic pain. The administration of UFP-512 increased/reestablished the spinal cord protein levels of Nrf2 and HO-1 in mice with inflammatory or neuropathic pain. However, while during inflammatory pain UFP-512 inhibited spinal c-Jun N-terminal kinase (JNK) and extracellular signal regulated kinase 1/2 (ERK1/2) phosphorylation induced by peripheral inflammation. This DOR agonist blocked the spinal activated PI3K/Akt signaling pathway under chronic neuropathic pain conditions, but it did not alter the enhanced protein levels of p-JNK or p-ERK1/2 induced by sciatic nerve injury. These results revealed the antinociceptive and antidepressant effects of UFP-512 in animals with chronic pain and the different mechanism of action of this DOR agonist in the presence of inflammatory or neuropathic pain. Our data also suggest the administration of UFP-512 as an alternative for the treatment of chronic pain and the depressive-like behaviors associated with neuropathic pain.

Selective delta agonists are said to have a cocaine-like stimulant effect in some experiments, but OTOH also morphine is a locomotor stimulant for cats so it's difficult to say how a selective delta ligand would affect a human.

 

[sekio]

A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol Cinzia Citti, Pasquale Linciano, Fabiana Russo, Livio Luongo, Monica Iannotta, Sabatino Maione, Aldo Laganà, Anna Laura Capriotti, Flavio Forni, Maria Angela Vandelli, Giuseppe Gigli & Giuseppe Cannazza
Scientific Reports volume 9, Article number: 20335 (2019)

A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ9-tetrahydrocannabinol: Δ9-Tetrahydrocannabiphorol - Scientific Reports

(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have...

www.nature.com

(-)-Trans-Δ9-tetrahydrocannabinol (Δ9-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ9-THC with a longer side chain have shown cannabimimetic properties far higher than Δ9-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ9-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)-trans-Δ9-tetrahydrocannabiphorol (Δ9-THCP). Along with Δ9-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ9-THCP against human CB1 receptor in vitro (Ki = 1.2 nM) resulted similar to that of CP55940 (Ki = 0.9 nM), a potent full CB1 agonist. In the cannabinoid tetrad pharmacological test, Δ9-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ9-THC.

So this is basically the opposite direction from THCV... neat.

 

[Blowmonkey]

Toxicology Letters
Volume 319, 1 February 2020, Pages 40-48

Cardiotoxic effects of [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol
Kyung SikYoonJin-MooLeeYoung-HoonKimSoo KyungSuhHye JinCha

Highlights

•
4-AcO-DET and 4-HO-MET prolonged QT intervals.
•
4-AcO-DET and 4-HO-MET inhibited potassium channels in the hERG assay.
•
4-AcO-DET and 4-HO-MET did not change PAK1 expression levels.

Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague–Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.

Cardiotoxic effects of [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol

Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-H…

www.sciencedirect.com

Quite self explanatory.

 

[S.J.B.]

Highlights

•
4-AcO-DET and 4-HO-MET prolonged QT intervals.
•
4-AcO-DET and 4-HO-MET inhibited potassium channels in the hERG assay.

Those are some fairly obscure tryptamines to study. I wonder if they tested a panel of others and these were the only ones that showed these effects.

 

[Blowmonkey]

I don't know, seems like they just arbitrarily picked 2 of the various 4-substituted tryptamines, I just saw it on another forum and thought it was weird enough myself to post it here. Not that scared of the results if we compare it to alcohol for example, how abusive are these two substances really? Still good to know I guess, you might drop dead if you take them and have pre-existing heart conditions.

 

[polymath]

In 1999 or 2000, someone with nickname "Village Idiot" wrote about a meth synthesis where O-acetylated ephedrine was reduced electrolytically with a noble metal cathode and an anode compartment separated with a semipermeable membrane... I just thought whether someone could produce desomorphine from acetylated morphine/codeine in the same way, that would avoid phosphorus and other toxins ending up in the product... Not going into details about this of course, and the Russian kitchen chemists probably don't want to spend $300+ for a platinum electrolytic plate.

 

[draculic acid69]

If you liked it, you should have put a methylene-dioxy ring on it.

ebola

Haha, nice

 

[Rectify]

So my days of being a guinea pig are over.
Of the 30+ drugs in this thread that I sampled, piperidin-4yl phenyl ether (ANDREW) was my favorite.
Even so, it had hints of what could be caused neurological strungies. Vertical nystagmus is a big plus though.
I was never allowed to try piperidin-4-yl 3,4-methylenedioxyphenyl ether (DISCO_CRISCO) Might have made me gay or something? I dunno.

All in all, I'd rather have an endless supply of Focalin (dexmethylphenidate) than any of it.

 

[S.J.B.]

Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)-N-phenylpiperidine-1-carboxamide as novel potent analgesic
Corresponding author: Wei Fu (Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai, China)
European Journal of Medicinal Chemistry 2020, Volume 189, Page 112070
Published online January 18th, 2020
https://doi.org/10.1016/j.ejmech.2020.112070

Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective μ opioid receptor (MOR) ligand 2a (Ki MOR: 7.3 ± 0.5 nM; Ki DOR: 849.4 ± 96.6 nM; Ki KOR: 49.1 ± 6.9 nM) as potent analgesic with ED50 of 3.1 mg/kg in 55 °C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over δ opioid receptor (DOR) and κ opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands.

Spoiler: MOR ligands

Unfortunately they do not comment on the stereochemistry, but my guess is that the (3-methoxy)phenyl and (dimethylamino)methyl groups are trans like in tramadol, or that a mixture of diastereomers is used with trans predominant.

 

[polymath]

^ Replace the piperidine nitrogen with a carbon and this target prediction says it could also be a cannabinoid agonist:

http://www.swisstargetprediction.ch/result.php?job=1104367956&organism=Homo_sapiens (tramadol)

http://www.swisstargetprediction.ch/result.php?job=944604024&organism=Homo_sapiens (compound 2a)

http://www.swisstargetprediction.ch/result.php?job=790648500&organism=Homo_sapiens (compound 2a with a carbon replacing piperidine nitrogen)

 

[sekio]

 

[checktest]

I remember seeing that! Oh god it was from 1999. Speaking of faux Hinterland Canadian videos.

 

[sekio]

Investigation of the Adrenergic and Opioid Binding Affinities, Metabolic Stability, Plasma Protein Binding Properties, and Functional Effects of Selected Indole-Based Kratom Alkaloids
Samuel Obeng, Shyam H. Kamble, Morgan E. Reeves, Luis F. Restrepo, Avi Patel, Mira Behnke, Nelson J.-Y. Chear, Surash Ramanathan, Abhisheak Sharma, Francisco León Takato Hiranita, Bonnie A. Avery, Lance R. McMahon, Christopher R. McCurdy
J. Med. Chem. 2020, 63, 1, 433-439
Publication Date: December 13, 2019

https://doi.org/10.1021/acs.jmedchem.9b01465

Selected indole-based kratom alkaloids were evaluated for their opioid and adrenergic receptor binding and functional effects, in vivo antinociceptive effects, plasma protein binding, and metabolic stability. Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), had higher affinity at opioid receptors than at adrenergic receptors while the vice versa was observed for corynantheidine. The observed polypharmacology of kratom alkaloids may support its utilization to treat opioid use disorder and withdrawal.

Interesting - speciocilatine is apparently an opioid too.

 

[Rectify]

I think

1-(pyrylium-4-yl)-2-aminopropane

may have given me brain damage. Persistent anxiety. Avoid.

 

[sekio]

non-sterically-masked pyrylium compounds are unstable in the presence of nucleophiles like water ot amines and would be useless as drugs in the human body

... but you knew that, right?

 

[sekio]