NSPD journal club

[polymath]

In another thread, I mentioned the possibility that the doubling of brain kynurenic acid levels by high doses of L-tryptophan (5 g/day) could possibly potentiate the effect of dissociatives, as kynurenate blocks the glycine binding site on NMDA receptors. Looking at some publications, it also seems that COX-1 inhibitors such as aspirin and paracetamol (acetaminophen) cause a similar increase in brain kynurenic acid concentration. In this article, this has been tested in rats with indomethacin. NMDAr glycine site blockers are also known to cause an anxiolytic effect, and this is also seen with paracetamol and aspirin, which makes me suspect that this effect of NSAIDs could be caused by them affecting metabolic kynurenate production. The anti-anxiety effect of paracetamol is usually attributed to its influence on endocannabinoid metabolism, but the kynurenic acid pathway could also be a factor in this. The possibility of aspirin or paracetamol potentiating the effect of ketamine, PCP and other dissociatives is somewhat significant, because someone could easily take that combination without knowing that there can be a synergistic effect.

Curiously, the non-steroidal anti-inflammatory drug indomethacin has also caused psychotic symptoms to some people, as have some other drugs of that class as well, and it wouldn't be surprising if this is caused by it affecting the NMDA receptor.

Edit: looks like there is this thread on BL about HA-966, which is an NMDA glycine site blocker or partial agonist.

 

[AlsoTapered]

Good point well made. It's so long since I was an undergrad. I remember Vogal's Textbook of Practical Organic Chemistry being a really useful resource.

https://ia800206.us.archive.org/19/items/TextbookOfPracticalOrganicChemistry5thEd/VogelPracticalOrganicChemistry5thEditionnewfoundV_text.pdf

 

[AlsoTapered]

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ibb.co

It's easy to draw things. Above is a bioisostere of mephedrone... but does anyone know of ANY route to actually synthesize it?

N-methyl-1-(4-methylphenyl)sulfonylethanamine

N-methyl-1-(4-methylphenyl)sulfonylethanamine | C10H15NO2S | CID 67983142 - structure, chemical names, physical and chemical properties, classification, patents, literature, biological activities, safety/hazards/toxicity information, supplier lists, and more.

pubchem.ncbi.nlm.nih.gov

It's even known. But again, I ask the simple question, how would one actually synthesize the compound?

And THAT is the truth of medicinal chemistry. It's very easy to draw a structure and even, using the appropriate tools, perform in-silico calculations concerning it's activity, but if you can't actually MAKE it, you can't confirm any activity nor patent it and much less assign a trivial name.

The PubChem article even refers to patents... and yet to the best of my knowledge, nobody has EVER made it.

 

[AlsoTapered]

UNODC - Bulletin on Narcotics - 1958 Issue 4 - 006

Braenden, Eddy & Halbach (1955), summarizing the relationship between chemical structure and analgesic action, said "In morphine and its derivatives the methyl substituent on nitrogen seems essential because its substitution by other alkyl groups reduces or abolishes analgesic action." It is...

www.unodc.org

Scroll down to the scanned images - these are levorphanol homologues with a variety of N-substituents. The second image lists:

Ro 4-1539 - ED50 0.010 (0.009-0.012) mg/kg

i.e. some x480 morphine in potency.

Ro4-1539 - Wikipedia

en.wikipedia.org

Now, their is a simply huge number of antagonists and partial agonists that may be N-dealkylated using non-classical Polonovski reactions (and other methodologies).

N-Dealkylation of Amines

N-dealkylation, the removal of an N-alkyl group from an amine, is an important chemical transformation which provides routes for the synthesis of a wide range of pharmaceuticals, agrochemicals, bulk and fine chemicals. N-dealkylation of amines is also ...

www.ncbi.nlm.nih.gov

One example would be the N-dealkylation of nalmefene. The N-methyl homologue of nalmefene is some x60 morphine* and so, based on known QSAR data, the N-2-(furan-2-yl)ethyl homologue (like Ro 4-1539) should be around x1600 morphine in potency.

*'Opiates' 1986 by Lenz et all: Page 63 'Structure-Activity Relation of Morphine and Related Structures' Table 3.3

Thus NALMEFENE represents a pre-precursor (2 steps) to:

17-(2-(futan-2-yl)ethyl)-4,5α-epoxy-6-methylenemorphinan-3,14-diol

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ibb.co

Later work by Professor Helmut Schmidhammer at the University of Innsbruck in the mid-1990s demonstrated that replacing the 14-hydroxy moiety for a 14-methoxy (such as 14-methoxy metopon) increased analgesic activity by almost 2 orders of magnitude. It is believed that this is a result of increased affinity for the DOR.

14-Methoxymetopon - Wikipedia

en.wikipedia.org

So while the QSAR has not been funny explored, it's possible that:

17-(2-(futan-2-yl)ethyl)-4,5α-epoxy-6-methylenemorphinan-14-methoxy-3-hydroxyl

Demonstrates even higher activity but careful examination of his would would be required. But, if it proved to be the case that this compound could in fact be over 100,000 times the activity of morphine. But I would consider a compound with such activity to be a chemical weapon first and foremost:

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ibb.co

I should add that a Canadian BLer has already found reference to a compounds that is estimated to be over 100,000x morphine it it's analgesic activity, likely due to possessing both MOR and DOR activity so the above does not represent a range of activity unknown to science.

 

[AlsoTapered]

I'd be interested in seeing that paper, then.

https://www.science.org/doi/10.1126/science.abk3099

So most certainly NOT relating to some magical route in the reduction of (pseudo)ephedrine to methamphetamine.

I remember long ago when quite a few members of 'The Hive' devoted much effort into the use of the Akabori reaction in an attempt to produce PPA. Variations were attempted but the consensus was 'if it looks too good to be true, it isn't true'. It worked, but the yields were low and it wasn't of any practical value.

No doubt lurkers were imagining that they could make a fortune out of selling 4MAR. Experience shows that it's VERY rare for an entire industry to entirely miss a cheaper methodology. As we know, L-PAC is the commercial precursor to PPA.

 

[AlsoTapered]

Development of 5-Substituted N-Methylmorphinan-6-ones as Potent Opioid Analgesics with Improved Side-Effect Profile

One of the most important functions of the opioid system is the control of pain. Among the three main opioid receptor classes (<i>μ</i>, <i>δ</i>, <i>κ</i>), the <i>μ</i> (MOR) is the main type targeted for pharmacotherapy of pain. Opioid analgesics such as morphine, oxycodone and fentanyl are...

www.hindawi.com

I consider the above to be the index paper of the work by Helmut Schmidhammer who looked into the 14 substitution of phenanthracine opioids. It's interesting to note that he uses several chemically unrelated MOR/DOR ligands and examines the increased activity of such compounds.

14-methoxymetopon demonstrates the classic 'magic methyl' problem that is the bane of medicinal chemists. While alternatives to his synthesis exist, they are based on recent advances in organic chemistry and all are problematic. As it is he was forced to use methyl iodide and sodium hydride to methylate the quaternary hydroxyl moiety.

I did try to find facile alternatives but all of them proved to be lower yielding than his route.

 

[AlsoTapered]

While I feel it should be the right of every adult to make an informed choice what compounds they choose to imbibe, I think INFORMED choice is vital.

The unapproved drug centrophenoxine (meclofenoxate) in cognitive enhancement dietary supplements - PubMed

Clinicians should be aware and advise patients that cognitive enhancement supplements may contain unapproved and prohibited drugs.

pubmed.ncbi.nlm.nih.gov

Now please forgive me for only providing one reference but it's a widely known issue within the supplement industry that their is very little oversight. It isn't an issue limited to centrophenoxine. I've read that even simple vitamin and electrolyte supplements often don't contain the stated dose and contain unlisted compounds.

If you can afford it, I strongly urge you to buy the pure material that is provided with a reliable, independent certificate of analysis.

While it's rare that supplements contain dangerous impurities, it's worth noting that some quite high-profile supplements have been taken off the market because unlike a medicine, the testing requirements for supplements are somewhat lax.

 

[AlsoTapered]

Diels–Alder Adducts of Morphinan-6,8-Dienes and Their Transformations

6,14-ethenomorphinans are semisynthetic opiate derivatives containing an ethylene bridge between positions 6 and 14 in ring-C of the morphine skeleton that imparts a rigid molecular structure. These compounds represent an important family of opioid receptor ...

www.ncbi.nlm.nih.gov

The mystery of 6,14-Endoethenotetrahydrooripavine.

The above link is a deep dive showing just how complicated the synthesis and isolation of etorphine actually IS. The truth is, it's unlikely to replace any of the black marked high-potency opioids soon.

But let's consider the first step. Thebaine (or in some cases oripavine) are reacted with a

dienophile noun di·eno·phile dīˈenəˌfīl
plural-s

definition:
the olefinic or acetylenic component (such as maleic anhydride) that is seeking a diene in the Diels-Alder reaction.

Now it's well known that 1,3-butandiene and ethene can be reacted to produce cyclohexene. There are MANY examples of this class of reaction being used to produce polymers. So one would think that the mystery compound would be a major product of oripavine and ethene. Not the ONLY product mind you because depending on the face being attacked, the -CH=C- bond could end up above or below the C-ring.

Now I actually DON'T think this is a major issue since hydrogenation yields the dihydro derivatives that appear to be uniformly more potent.

So potentially,, a compound listed as being some x400 morphine in potency is just two steps from oripavine (which isn't mentioned in the UNODC list of controlled drugs and seeminly isn't a controlled precursor.

So IF I had to guess, I would guess that...

(6R)-11hydroxy-15-methoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-triene

AKA

6,14-hexahydrooripavine

WILL be a reasonable candidate.

614H

 

[Rectify]

3-carbonyl-indole to 4-acetoxy-3-carbonyl-indole

https://pubs.acs.org/doi/10.1021/acs.orglett.3c03568

 

[shapeshifter32]

Everything we know about the 5-HT2A (serotonin) receptor

Read our ultimate guide to the 5-HT2A serotonin receptor. Discover the pharmacology and physiology of 5-HT2A in the nervous and cardiovascular systems.

www.reprocell.com

 

[Rectify]

Visible-light-driven synthesis of N-heteroaromatic carboxylic acids by thiolate-catalysed carboxylation of C(sp²)–H bonds using CO2 - Nature Synthesis

The catalytic carboxylation of C(sp2)–H bonds using CO2 is an efficient strategy to produce carboxylic acids; however, the carboxylation of azines is a challenge. Now, a visible-light-driven, thiolate-catalysed method for the carboxylation of azine C(sp2)–H bonds using CO2 is reported, enabling...

www.nature.com

 

[Rectify]

On The Quest For Better Antibiotics: This Fairly Recent Article Indicates That The Major Component Of Grapefruit Essential Oil (EO) Is Limonene. The Antimicrobial Effects Of Various Chemical Compounds Found In The EO Of Grapefruit Are Discussed. This EO Has Also Been Shown To Potentiate Certain Drugs.

Chemical Composition, Antimicrobial, Antioxidant, and Antiproliferative Properties of Grapefruit Essential Oil Prepared by Molecular Distillation

Grapefruit essential oil has been proven to have wide range of bioactivities. However, bioactivity of its molecular distillate has not been well studied. In this study, a light phase oil was obtained by molecular distillation from cold-pressed grapefruit ...

www.ncbi.nlm.nih.gov

 

[Rectify]

I think made a mistake on Step 9.

The reaction of a nitrile with LAH in ether gives the amine without sigma bond breakage.

Conversion of nitriles to 1° amines using LiAlH4

Nitriles can be converted to 1° amines by reaction with LiAlH4. During this reaction the hydride nucleophile attacks the electrophilic carbon in the nitrile to form an imine anion. Once …

chem.libretexts.org

AlsoTapered, is that right?

I know plain old H3O+ / dell (reflux) will do it, but it might take off the N-formyl group, too, yielding the following after carboxy O-methylation [Step 10]:

THE_INCREDIBLE_HULK
1-(3,4-dichlorophenyl)-1-carbomethoxy-2-aminopropane

Bon Apetit!

 

[Rectify]

These Product N-N's Are Going To Be Explosive, I Would Think.

Organocatalytic diastereo- and atroposelective construction of N–N axially chiral pyrroles and indoles - Nature Communications

N–N axially chiral motifs are of synthetic interest due to their presence in natural products, pharmaceuticals, and chiral ligands. Here, the authors develop a direct catalytic synthesis of N–N atropisomers with simultaneous creation of contiguous axial and central chirality by oxidative NHC...

www.nature.com

 

[AlsoTapered]

Library Genesis

libgen.li

There's the paper on the long-acting derivatives.

One could patent it's use in the treatment of opioid dependence. I'm a medicinal chemist, not a clinician so it's not something I could do.

BTW I think I NEED to say this. The picture you see of a molecule is a diagram, not an image. Complex chemicals are 3D structures and however you do it, if you attempt to display such a thing in 2D it is inevitably an estimation at best. I say this because it's apparent some people don't 'get' optical isomerism much less things like molecular overcrowding that results in multiple enantiomers. That's not an insult - some people have lives... I just have organic chemistry.

 

[Psychestim]

https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00082

 

[Skorpio]

Sweet, a new scaffold! I wonder how the subjective effects are, as (to my knowledge) it is unclear if more selective agonists of 5HT2A produce subjectively less "rich" experiences.