Ketamine salts solubility

[sekio]

Also, the bare phenyl version might be nice.

The "bare phenyl" is called tropacocaine and there have been pamphlets suggesting it might be a "legal coke replacement". I don't think the pharmacology points to them being abusable drugs though, I believe that tropacocaine & its more "druglike" p-fluoro analog are both stronger as sodium-channel blocking anesthetics than monoamine reuptake inhibitors. It does occur naturally in coca though, in some small amount.

The phenyl ether of pseudotropine, and in fact many other pseudotropine aryl ethers, are also active as monoamine transporter ligands, but I believe they are rather long duration and more selective for NE than others. (Actually I am told that pseudotropine phenyl ether led to at least one individual having a fatal stroke, back in Ye Olde Days...)

 

[AlphaMethylPhenyl]

That said, it's always a task to differentiate the studies on nicotine from those on the tobaccy. They're way too often conjoined and thought of as one. Commercial tobacco and nicotine are different. It's like weed isn't CBD or THC.

 

[polymath]

So looks like there is some actual proof about the harmful effects of nicotine itself... Is this some unspecific effect of nicotine or is it a direct result of binding to nicotinic receptors? Another nicotine agonist that is found in nature is the arecoline in Betel nut, but that compound is also a muscarine agonist to some extent.

 

[Dresden]

JIM "CRAWFORD" EMERY

 

[Dresden]

SID

If You Don't Know Sid, Then You Don't Know Jack.

P --> Q
~Q --> ~P

 

[Dresden]

That's why the ideal age to have kids is age 23. Cigarettes are for people who aren't afraid to die, for it is by dying that we awaken to life everlasting.

 

[AlphaMethylPhenyl]

So looks like there is some actual proof about the harmful effects of nicotine itself... Is this some unspecific effect of nicotine or is it a direct result of binding to nicotinic receptors? Another nicotine agonist that is found in nature is the arecoline in Betel nut, but that compound is also a muscarine agonist to some extent.

In mice. I wouldn't advocate pregnant women smoking, or anyone for that matter, but back in the 50's just about everyone smoked. And that was for hundreds of years, since the 1500's, if I recall right. Now, understanding that there might be more unhealthy additives today as opposed to back then, I still think that the pure plant isn't quite neurologically toxic. For example, so many of the groundbreaking philosophers in The Enlightenment were smokers, which itself really began in the 1500's. I don't quite buy the "well they would have been even better without it" theory.

As far as I'm aware, all tobacco has specific nitrosamines that makes the plant carcinogenic (without additives). But in terms of causing dementia/Alzheimers, I remain skeptical.

Since smoking once upon a time was everywhere, perhaps people sitting in their dens/man caves of then would think better while smoking there, but run a little deficit otherwise, which might explain smokers having compromised cognition in studies wherein they weren't smoking. It's like caffeine. It still works to an extent even if you're addicted, yet sets you at a disadvantage without it.

 

[clubcard]

First they ignore you, then they laugh at you, then they fight you, then you win.
paraphrasing Klein

the DEA was probably at the laughing stage. Secretly they were very inpressed with your chemical prowess and the way you propose magically transmuting Nitrogen to Carbon without a nuclear reactor.

The DEA know 2-amino oxazoles are theoretically possible from L PAC via cyanamide The reduction of an amino oxazole to amino oxazoline is not straightforward and the chiral center of L-PAC would not be preserved in the amino oxazole. The DEA reads Sciencemadness and they read all of The Hive.

I will dig out the original East German patent from the 1970s. Their yield isn't great but they claim it produces the chiral product. They do not show how the reaction proceeds but it certainly didn't require a reduction. If I remember correctly it required a strict 1:2 stoichiometric ratio and I believe that the second step (that at the time was termed as 'preparation' and translated as 'workup' used KOH and yielded the product and KCN. It's on the Eunoia Disc so I would expect them to have seen it. There is also a Polish paper on phenyloxirane --> aminorex in a single step using NaHNCN. Not a great yield and probably hard to workup but god it's cheap.

 

[novaveritas]

I will dig out the original East German patent from the 1970s. Their yield isn't great but they claim it produces the chiral product. They do not show how the reaction proceeds but it certainly didn't require a reduction. If I remember correctly it required a strict 1:2 stoichiometric ratio and I believe that the second step (that at the time was termed as 'preparation' and translated as 'workup' used KOH and yielded the product and KCN. It's on the Eunoia Disc so I would expect them to have seen it. There is also a Polish paper on phenyloxirane --> aminorex in a single step using NaHNCN. Not a great yield and probably hard to workup but god it's cheap.

L-PAC plus cyanamide gives the oxazole not the oxazoline, 2-amino-4-methyl-5-phenyloxazole. Didehydro 4-MAR. This has a double bond and results in the loss of chirality. see US3052688 example 6 that is a 1962 US version of German patent.

so what is the product supposed to be? it isn't the structure you drawed.

that is why the DEA were not interested. they think you are full of it

styrene oxides to aminorex is old but the route uses guanidine not cyanamide.
what is the eunoia disc? sounds like Uncle Fester for the new millenium

 

[polymath]

In mice. I wouldn't advocate pregnant women smoking, or anyone for that matter, but back in the 50's just about everyone smoked. And that was for hundreds of years, since the 1500's, if I recall right. Now, understanding that there might be more unhealthy additives today as opposed to back then, I still think that the pure plant isn't quite neurologically toxic. For example, so many of the groundbreaking philosophers in The Enlightenment were smokers, which itself really began in the 1500's. I don't quite buy the "well they would have been even better without it" theory.

Yeah, I think that in the 18th century there were many places in the world where almost no one smoked tobacco, but things like calculus and classical mechanics were still developed first in Europe where smoking was common. It may be that nicotine exposure just makes it more likely for one to produce ADHD offspring but doesn't affect the likelyhood of genius children being born.

In the future, it will be possible to do gene edits that improve intelligence - for instance the deletion of the gene that codes the alpha5 subunit of GABA-A receptor improves memory and learning in lab rats without causing any obvious harmful effects. But of course, before doing such gene deletions to people it would be safest to first try to find some rare individual who happens to have such a mutation by random (in nuclear disaster sites there are probably many people with unusual mutations) and see whether they suffer from any harmful side effects. Just writing this because of the recent news about gene edited babies in China...

 

[AlphaMethylPhenyl]

Wow, didn't know about that in China. Not terribly surprised that they would do so. What I do know is that clones die much quicker than naturally-conceived animals, three times as fast. Gene editing is a huge moral can of worms, for one.

 

[polymath]

There are now some methods to change the genes of an adult person, too. I think some "biohacker" already tested it on himself. It's likely that there will be plenty of willing guinea pigs for that kind of thing, including athletes who want to increase their physical performance.

 

[sekio]

How about a retrovirus that patches the Vitamin C synthesis enzyme (L-gulonolactone oxidase) back to working order. That'd be cool, being able to produce multiple grams of VitC a day with no need for supplementation.

Or make a baby that produces green fluorescent protein in his skin. Fluorescent baby. Or make the sclera of the eyes produce a blue fluorescent protien and you can make a race of Fremen from Dune.

 

[polymath]

An even better "sci-fi" gene edit would be to add the tardigrade radiation tolerance gene to human DNA, so that people could withstand long-term space travel...

DNA Protection Protein, a Novel Mechanism of Radiation Tolerance: Lessons from Tardigrades

Genomic DNA stores all genetic information and is indispensable for maintenance of normal cellular activity and propagation. Radiation causes severe DNA lesions, including double-strand breaks, and leads to genome instability and even lethality. Regardless of the toxicity of radiation, some organisms exhibit extraordinary tolerance against radiation. These organisms are supposed to possess special mechanisms to mitigate radiation-induced DNA damages. Extensive study using radiotolerant bacteria suggested that effective protection of proteins and enhanced DNA repair system play important roles in tolerability against high-dose radiation. Recent studies using an extremotolerant animal, the tardigrade, provides new evidence that a tardigrade-unique DNA-associating protein, termed Dsup, suppresses the occurrence of DNA breaks by radiation in human-cultured cells. In this review, we provide a brief summary of the current knowledge on extremely radiotolerant animals, and present novel insights from the tardigrade research, which expand our understanding on molecular mechanism of exceptional radio-tolerability.

 

[polymath]

Here's a new article about functionally selective kappa agonists (apparently there's two different secondary messengers that can be activated by binding).

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice Int J Neuropsychopharmacol. 2018 Sep; 21(9): 847?857.

Abstract

Background
The kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).

Methods

BPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.

Results

BPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.

Conclusions

BPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

I'm not sure about which kind of functional selectivity is behind the salvia-type hallucinogenic effects, but the compound B (BPHA) would seem to be relatively easy to produce synthetically. However, that's the one compound that caused least motor incoordination.

Is there any SAR available for those phenylacetic amide compounds D and E?

 

[polymath]

It was already known in the 1990s that neuropeptide FF receptor blockers prevent opioid tolerance, but now there's a compound with both effects in one.

A bifunctional-biased mu-opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects. Pain. 2018 Sep;159(9):1705-1718. doi: 10.1097/j.pain.0000000000001262.

Abstract

Opioid analgesics, such as morphine, oxycodone, and fentanyl, are the cornerstones for treating moderate to severe pain. However, on chronic administration, their efficiency is limited by prominent side effects such as analgesic tolerance and dependence liability. Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are recognized as an important pronociceptive system involved in opioid-induced hyperalgesia and analgesic tolerance. In this article, we report the design of multitarget peptidomimetic compounds that show high-affinity binding to the mu-opioid receptor (MOPr) and NPFFRs. In vitro characterization of these compounds led to identification of KGFF03 and KGFF09 as G-protein-biased MOPr agonists with full agonist or antagonist activity at NPFFRs, respectively. In agreement with their biased MOPr agonism, KGFF03/09 showed reduced respiratory depression in mice, as compared to the unbiased parent opioid agonist KGOP01. Chronic subcutaneous administration of KGOP01 and KGFF03 in mice rapidly induced hyperalgesia and analgesic tolerance, effects that were not observed on chronic treatment with KGFF09. This favorable profile was further confirmed in a model of persistent inflammatory pain. In addition, we showed that KGFF09 induced less physical dependence compared with KGOP01 and KGFF03. Altogether, our data establish that combining, within a single molecule, the G-protein-biased MOPr agonism and NPFFR antagonism have beneficial effects on both acute and chronic side effects of conventional opioid analgesics. This strategy can lead to the development of novel and potent antinociceptive drugs with limited side effects on acute and chronic administration.

 

[Dresden]

RHODES CARDAMON

DOLEN KETO

It's A Shiny, Shiny Day.

CARDI B.

A Pentagon.

 

[sekio]

Sulforaphane Inhibited the Nociceptive Responses, Anxiety- and Depressive-Like Behaviors Associated With Neuropathic Pain and Improved the Anti-allodynic Effects of Morphine in Mice
Pablo Ferreira-Chamorro, Alejandro Redondo, Gabriela Riego, Sergi Le?nez and Olga Pol
https://www.frontiersin.org/articles/10.3389/fphar.2018.01332/full

Our results showed that the repeated administration of SFN besides inhibiting nociceptive responses induced by sciatic nerve injury also diminished the anxiety- and depressive-like behaviors associated with persistent neuropathic pain. Moreover, SFN treatment normalized oxidative stress by inducing Nrf2/HO-1 signaling, reduced microglial activation and JNK, ERK1/2, p-38 phosphorylation induced by sciatic nerve injury in the spinal cord and/or hippocampus and prefrontal cortex. Interestingly, treatment with SFN also potentiated the antiallodynic effects of morphine in sciatic nerve-injured mice by regularizing the down regulation of MOR in the spinal cord and/or hippocampus. This study suggested that treatment with SFN might be an interesting approach for the management of persistent neuropathic pain and comorbidities associated as well as to improve the analgesic actions of morphine.

Eat your broccoli, folks.

 

[sekio]

going to rename this to the "dresden teaches preschoolers shapes" thread /s

 

[Dresden]

Haha!

DREW LONG

FITZ G.

J.B.

MAXWELL

Good To The Last D-R-O-P .

HOWARD

CCR