Ketamine salts solubility

[S.J.B.]

Discovery of dual-acting opioid ligand and TRPV1 antagonists as novel therapeutic agents for pain
Corresponding author: Jeewoo Lee (Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul, South Korea)
European Journal of Medicinal Chemistry 2019, Volume 182, Page 111634
Published online August 21st, 2019
https://doi.org/10.1016/j.ejmech.2019.111634

In order to discover a novel type of analgesic, we investigated dual activity ligands with TRPV1 antagonism and mu-opioid receptor affinity with the goal of eliciting synergistic analgesia while avoiding the side effects associated with single targeting. Based on a combination approach, a series of 4-benzyl-4-(dimethylamino)piperidinyl analogues were designed, synthesized and evaluated for their receptor activities. Among them, compound 49 exhibited the most promising dual-acting activity toward TRPV1 and the mu-opioid receptor in vitro. In vivo, 49 displayed potent, dose-dependent antinociceptive activity in both the 1st and 2nd phases in the formalin assay. Consistent with its postulated mechanism, we confirmed that in vivo, as in vitro, compound 49 both antagonized TRPV1 and functioned as a mu-opioid agonist. This result indicates that dual-acting TRPV1 antagonist/mu-opioid ligands can be made and represent a new and promising class of analgesic.

 

[negrogesic]

Look at this bad boy N-(DOM)fentanyl, or 2',5'-dimethoxy 4'-methyl α-methyl fentanyl, cayman sells it...

 

[blueberries]

It took me three pages before I started getting this thread. It works though, I'll give you that!

PS: ^^^THE TURTLE KING

 

[Rectify]

JAMES SEVEN
pyrylium-4-yl 1-ethyl-3-carbomethoxy-piperidin-4-yl ether

And Now, Ladies & Gentlemen, To Answer Your Most Burning Question: How Did I--Loursy Me--Get To Try Approximately 36 Different Drugs In This Thread Which I Designed Over The Past Year?

Easy: D.E.A. Schedule I Permit, Bebe!!!

Let's Just Say I Have "Friends" In High Places.



Lazy Eye, No Lie.

* * *

 

[negrogesic]

And Now, Ladies & Gentlemen, To Answer Your Most Burning Question: How Did I--Loursy Me--Get To Try Approximately 36 Different Drugs In This Thread Which I Designed Over The Past Year?

Easy: D.E.A. Schedule I Permit, Bebe!!!

Let's Just Say I Have "Friends" In High Places.



Lazy Eye, No Lie.

* * *

Really?

 

[Rectify]

Yes.

It Pays To Discover.

 

[Rectify]

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

 

[negrogesic]

Yes.

It Pays To Discover.

Its obviously difficult to believe (no offense intended, but if true, very interesting). Which compounds did try? (Not much on here is schedule I from what I recall, but some starting materials would be tricky to come by.)

 

[Rectify]

2,5-DM-3,4-MDA.hcl is Schedule I. (with 150mg per os; it gave me a HEADACHE; too many O's!)
Ethylamphetamine is Schedule I. (My favorite drug so far.)

I just recently posted a SHIVA and an ANDREW trip report in the appropriate forum. Yes, they are not (yet) Schedule I drugs.

More Will Be Revealed. I am on James Seven now. Ciao. Tris. Auf Wiedersehen. Hasta la vista. Adieux. Adios. Goodbye. bye bye. Tris.

 

[checktest]

The Neuroscience of Drug Reward and Addiction
Corresponding author:
Nora D. Volkow, Michael Michaelides, and Ruben Baler
National Institute on Drug Abuse, Bethesda, Maryland
Physiological Reviews 2019 99:4, 2115-2140
Published in print 1 October 2019

https://doi.org/10.1152/physrev.00014.2018

Drug consumption is driven by a drug’s pharmacological effects, which are experienced as rewarding, and is influenced by genetic, developmental, and psychosocial factors that mediate drug accessibility, norms, and social support systems or lack thereof. The reinforcing effects of drugs mostly depend on dopamine signaling in the nucleus accumbens, and chronic drug exposure triggers glutamatergic-mediated neuroadaptations in dopamine striato-thalamo-cortical (predominantly in prefrontal cortical regions including orbitofrontal cortex and anterior cingulate cortex) and limbic pathways (amygdala and hippocampus) that, in vulnerable individuals, can result in addiction. In parallel, changes in the extended amygdala result in negative emotional states that perpetuate drug taking as an attempt to temporarily alleviate them. Counterintuitively, in the addicted person, the actual drug consumption is associated with an attenuated dopamine increase in brain reward regions, which might contribute to drug-taking behavior to compensate for the difference between the magnitude of the expected reward triggered by the conditioning to drug cues and the actual experience of it. Combined, these effects result in an enhanced motivation to “seek the drug” (energized by dopamine increases triggered by drug cues) and an impaired prefrontal top-down self-regulation that favors compulsive drug-taking against the backdrop of negative emotionality and an enhanced interoceptive awareness of “drug hunger.” Treatment interventions intended to reverse these neuroadaptations show promise as therapeutic approaches for addiction.

Full text available from researchgate author profile

https://www.researchgate.net/publication/336181368_The_Neuroscience_of_Drug_Reward_and_Addiction

Decent general review.

 

[polymath]

A new four amino acid peptide mu agonist...

https://www.pnas.org/content/116/44/22353

Zoltan Dekan, Setareh Sianati, Arsalan Yousuf, Katy J. Sutcliffe, Alexander Gillis, Christophe Mallet, Paramjit Singh, Aihua H. Jin, Anna M. Wang, Sarasa A. Mohammadi, Michael Stewart, Ranjala Ratnayake, Frank Fontaine, Ernest Lacey, Andrew M. Piggott, Yan P. Du, Meritxell Canals, Richard B. Sessions, Eamonn Kelly, Robert J. Capon, Paul F. Alewood, MacDonald J. Christie, A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor, Proceedings of the National Academy of Sciences Oct 2019, 116 (44) 22353-22358; DOI: 10.1073/pnas.1908662116

An Australian estuarine isolate of Penicillium sp. MST-MF667 yielded 3 tetrapeptides named the bilaids with an unusual alternating LDLD chirality. Given their resemblance to known short peptide opioid agonists, we elucidated that they were weak (Ki low micromolar) μ-opioid agonists, which led to the design of bilorphin, a potent and selective μ-opioid receptor (MOPr) agonist (Ki 1.1 nM). In sharp contrast to all-natural product opioid peptides that efficaciously recruit β-arrestin, bilorphin is G protein biased, weakly phosphorylating the MOPr and marginally recruiting β-arrestin, with no receptor internalization. Importantly, bilorphin exhibits a similar G protein bias to oliceridine, a small nonpeptide with improved overdose safety. Molecular dynamics simulations of bilorphin and the strongly arrestin-biased endomorphin-2 with the MOPr indicate distinct receptor interactions and receptor conformations that could underlie their large differences in bias. Whereas bilorphin is systemically inactive, a glycosylated analog, bilactorphin, is orally active with similar in vivo potency to morphine. Bilorphin is both a unique molecular tool that enhances understanding of MOPr biased signaling and a promising lead in the development of next generation analgesics.

 

[blueberries]

I originally started with the name "Phenomenal" and worked around that; I may try "Fantastic" or "Incredible" next!!

 

[negrogesic]

2,5-DM-3,4-MDA.hcl is Schedule I. (with 150mg per os; it gave me a HEADACHE; too many O's!)
Ethylamphetamine is Schedule I. (My favorite drug so far.)

I just recently posted a SHIVA and an ANDREW trip report in the appropriate forum. Yes, they are not (yet) Schedule I drugs.

More Will Be Revealed. I am on James Seven now. Ciao. Tris. Auf Wiedersehen. Hasta la vista. Adieux. Adios. Goodbye. bye bye. Tris.

How is ethylamphetamine? Isn't it primarily dopaminergic? Does it have any noradrenergic push? Dopamine releasers are usually dogs as far as recreational drugs are concerned (but can be decent functional stimulants with profound antidepressants effects).

 

[Rectify]

ETH: Speedy, slightly entactogenic, speedy, awesome.

VANILLA ICE
1-(2,4-dichlorophenyl)-2-aminopropane

 

[negrogesic]

ETH: Speedy, slightly entactogenic, speedy, awesome.

Are you aware of ethylamphetamine's ki values for DA/NE/5HT offhand?

 

[Rectify]

No, but I sure did enjoy it.

MIGHTY DAWG
1-(4-isopropyl-2-methoxyphenyl)-2-aminopropane

HOT DAM
1-(2,6-dimethoxy-4-isopropylphenyl)-2-aminopropane

BROLICIOUS
1-(3-chloro-4-bromophenyl)-2-methylaminopropane

TRISTAN
1-(4-methyl-5-methoxyindol-3-yl)-2-(methylpropylamino)ethane

CASSIE
1-(1-pentyl-4-methylindol-3-yl)-1-oxo-2-aminopropane

As I Understand It, The 12--one for each tribe of Israel--Best, Least Toxic Fruits Of The Spirit Will Be Selected At The Appropiate Time. God Has Promised Us That He Will Pour Out His Spirit(s) At Some Point, To Both Masters And Servants Alike.

Your Young Men Will Have Visions, And Your Old Men Will Dream Dreams.

And the kratom related El Shaoshyant of course. Oh yes. It was then that I realized that if the 4th dimension is TIME, then the 5th is COLOR. The 6th? SCENT.

ENZOSOAMINE, an anti-psychotic.
11-(1-(2-hydroxyethyl)piperidin-4-yl)-8-methoxydibenzo-1,4-diazepine

SVELTEINGTON
3-(1-oxoethyl)-1,2,3,4,5,6,7,N-octahydroindolo[2,3-a]quinolizin-2-yl (3,4-methylenedioxyphenyl) ether

There Is Something Good Waiting Down This Road. I Am Picking Up Whatever Is Mine.

FREE WILLY
N-pentyl-3-(1-oxoethyl)-7-oxo-1,2,3,4,5,6-hexahydroindolo[2,3-a]quinolizin-2-yl phenyl ether

One Ain't Nuttin' But One To The Three And One One One Ain't Nuttin' But One To The Three And One One One.

"It's Not Rocket Science. It's Just Science For Rockets."--Chance.

Please Hear Me Out: According To The Zoroastrians Of Iran, The Tree Of Life In The Garden Of Eden Produced A Substance (Haoma) Now Identified As Ephedrine As Its Fruit. Is That Correct? Idk. But I Suspect So. Ephedrine Can Be Reduced To 2-Methylamino-1-phenylpropane (methamphetamine) Or O-methylated To A Drug I Dubbed Methusaleh--Both Of Which I Have Tried And Found To Be Several Times Stronger Than Ephedra. A Penny For Your Thoughts?

HOUDINI
1-(3,4,5-trimethoxyphenyl)-1-methoxy-2-aminoethane

BIGGIE SMALLS (a WINNER All Day)
1-ethyl-3-carbomethoxypiperidin-4-yl phenyl ether

Sound Tribe Sector 9s
N-desmethyl-3-phenylmethanonyl-2-carbomethoxytropane

 

[S.J.B.]

Discovery of Novel Biased Opioid Receptor Ligands through Structure‐Based Pharmacophore Virtual Screening and Experiment
Corresponding authors: Yong-Chul Kim (Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Buk-gu, South Korea) and William A. Goddard, III (Materials and Process Simulation Center, California Institute of Technology, Pasadena, United States)
ChemMedChem 2019, Volume 14, Issue 20, Pages 1783-1794
Published online September 26th, 2019
https://doi.org/10.1002/cmdc.201900418

Gi‐protein‐biased agonists with minimal β‐arrestin recruitment represent opportunities to overcome the serious adverse effects of human mu opioid receptor (μ‐OR) agonists and developing alternative and safe treatments for pain. In order to discover novel non‐morphinan opioid receptor agonists, we applied hierarchical virtual screening of our in‐house database against a pharmacophore based on modeling the active conformations of opioid receptors. We discovered an initial hit compound, a novel μ‐OR agonist with a pyrazoloisoquinoline scaffold. We applied computational R‐group screening to this compound and synthesized 14 derivatives predicted to be the best. Of these, a new Gi‐protein‐biased compound, 1‐{5‐(3‐chlorophenyl)‐7,8‐dimethoxy‐3‐[4‐(methylsulfonyl)benzyl]‐3H‐pyrazolo[3,4‐c]isoquinolin‐1‐yl}‐N,N‐dimethylmethanamine, showed an EC50 value of 179 nm against the μ‐OR. This resulted in significant pain relief for mice in the phase II period of formalin response tests. This study provides a new strategy to identify diverse sets of promising compounds that might prove useful for the development of drugs that target other G‐protein‐coupled receptors.

The most potent compound in the series at the mu opioid receptor:

 

[Meth novice 79]

I’m not sure how it might have made it onto ancient Iranian history since I believe it’s native to Europe and the Africa’s.

But I did just read it was used as a medicine by native populations all over the world so maybe they traded it?

Personally it pisses me off. You almost have to sell your soul for it here in Aus cos everyone kept using it to make meth lol
Now they sell pseudo mostly only which is absolutely useless lol

The best meth I ever had was ephedrine based tho. I was lucky enough to get it just once.
I hate my government lol

 

[sekio]

pseudoephedrine is a good decongestant, poor stimulant tho

 

[Rectify]

CAINE
4-carbomethoxy-piperidin-4-yl phenyl ether

THE SMITHS
4-carbomethoxy-piperidin-4-yl 3,4-methylenedioxyphenyl ether

ALLEGRA (not to be confused with the antihistamine)
4-(3-chlorophenyl)-4-carbomethoxy-(1-methyl-2-phenylethyl)-piperidine

Expected to be PAF (potent as f*ck)