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Recreational Potential of Endocannabinoids

^ But if these compounds were legal, there would be a huge market for people who want to get high without breaking the law.
 
I am shpongled said:
^ But if these compounds were legal, there would be a huge market for people who want to get high without breaking the law.
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they almost certainly would be illegal in the US as analogues,
other countries they would on the whole be legal or quasi legal.
the next question is how long before they are made illegal if they become widely used?
 
all cannabinoids can be made water soluble by esterifying the phenol oxygen with a nitrogen-containing group, like in the synthetic cannabinoid Nabitan.

180px-Nabitan.png


just pop a HCl on there and you're set.
 
wungchow said:
all cannabinoids can be made water soluble by esterifying the phenol oxygen with a nitrogen-containing group, like in the synthetic cannabinoid Nabitan.

just pop a HCl on there and you're set.
Click to expand...

that of course also contains mechoulams tetrahydropyridine motif..
 
I've been administered water-soluble synthetic cannabinoids in trial tests, IV - unfortunately I can not find the structure or name of it anymore.
I found the effects very similar to cannabis but a little more idiosyncratic: it had it's own character. It was sedating and I got pretty high off it, at one point we got a lunch break from the constant testing and I probably had the biggest laughing fit I ever had preparing some sandwiches - I remember it was truly hilarious, I normally don't get that from cannabis, my housemate who was also a test subject received a placebo that day so he didn't find it nearly as funny ;)
The compound was tried for anaesthetic value to be applied for clinical dayoperations and the like but I heard it didn't come through.
I also participated in another cannabinoid test. Another test subject in the group frenzied on it, he couldn't stop running up and down the hallway of the facility mowing his arms. They took him to the emergency room where he pissed a gallon or so...
Afterwards they said it had not been threatening, more like an anxiety attack or mild allergy. The guy hadnt smoked pot ever before.
The rest of that trial got cancelled, so we all got to go home receiving full amount for it.

That was nice - getting paid to get high
 
Dr.Heckyll said:
Considering the difficult and thus costly synthesis of good cannabinoids and the wide availability of THC from cannabis plants at a reasonable price, I doubt that synthetic cannabinoids are economically viable. The competition from cannabis is too strong.
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Interesting how wrong some predictions were (not picking on you, just the first quote to the effect I found)- the entire time this discussion was ongoing, synthetic cannabinoids were being sold by the boat load.
 
I don't understand where he got the idea that cannabis-derived cannabinoids were economical. Synthetics are an order of magnitude cheaper per dose, even the ones that aren't active in micrograms.
 
Hammilton said:
Interesting how wrong some predictions were (not picking on you, just the first quote to the effect I found)- the entire time this discussion was ongoing, synthetic cannabinoids were being sold by the boat load.
Click to expand...
LOL! Exactly my thoughts, too... :\
 
One-step anandamide synthesis from 2 commercially available chemicals. My thought was this lipid material could be vaped in a water aerosol mist & absorbed by the lipid-rich linings of the lungs. Relatively simple lab requirements. The unreacted monoethanolamine & acid acceptor salt could be washed out of the reaction mix with cold water. I'd check the literature for methods used to purify anandamide itself but I would try to stay away from flammable solvents & high temperatures just to be on the safe side. Purity would largely depend on the purity of the 2 starting materials.

Graphic done with Chem Draw Professional 17.

m8owpshm3


Anandamide_synthesis.jpg
 
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Here is an alternate scheme involving using the methyl ester as the starting material & removing methanol via a distillation flask.

Anandamide_synthesis-2.jpg
 
SAR studies have shown that reversing the position of the carbonyl & amide nitrogen groups produces so-called retro-anandamides with more potent receptor binding affinity.

AM1174.jpg
 
SAR studies have produced other more potent anandamide derivatives such as ACPA where the ethanolamine function is replaced with a cyclopropyl amine group:
ACPA.jpg



The 4 cis double bonds are required for full activity.
 
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Has much work been done on the intrinsic efficacy/functional selectivity of endogenous cannabinoids and synthetic analogs? I'm seeing a lot about SAR with regards to affinity here but no mention of intrinsic efficacy - are the endogenous cannabinoids functionally different from e.g. THC?

Also, with that amount of pictures, you may want to link URLs or find a way to shrink the images for the sake of people's scrolling through the thread ;)

CY
 
I haven't studied the SAR here in any great depth. What gets me excited is my thought that these lipids could be probably administered via a water mist from an inexpensive home nebulizer. What also has me interested is the inexpensive availability of the so-called omega-3 fatty acids. Here we find analagous molecules with 3, 4 & even 5 & 6 cis double bonds that could conceivably be converted to a mixture of analogs of that potent N-cyclopropyl amine-tipped ACPA I posted above without having to go to the bother of isolating the individual acids. See list in table:

Omega-3_fatty_acids.jpg


I get your point about all the pretty pictures. I will not go to the effort of drawing all the N-cyclopropyl amides of all the acids in that table because anyone seeing the existing pictures can see what I mean from this table.
 
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Recent publication identifies AM4054 as a potent CB1 receptor agonist with considerably more potency than delta-9-THC:

AM4054.jpg


Here is the URL for the full-text article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4972635/ and the synthesis is described in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706088/ starting from 2,6-dimethoxyphenol. This material is known as syringol & finds use in flavor & fragrance formulations because it is described as having a strong smoky odor. Just scanning the details of the chemistry indicates that only a fully staffed & equipped lab would be able to make this even if you had the starting material.

Older CB1 agonists employ a 1,1-dimerthylheptyl side chain to prevent enzymatic oxidation of the carbon atom alpha to the aromatic ring. The 1-adamantanyl group apparently serves the same purpose but much more effectively.
 
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You never know what you might find if you poke around the internet in a focused search. I am obviously interested in cannabinoids & endocannabinoids & their mimetics but I am not in a position to get involved with trying to make any of these molecules. So it was a surprise to find that at least one of these molecules occurs naturally in the seeds of a rare pine tree:

Biol Pharm Bull. 2000 Jun;23(6):758-61.
Occurrence of a novel cannabimimetic molecule 2-sciadonoylglycerol (2-eicosa-5',11',14'-trienoylglycerol) in the umbrella pine Sciadopitys verticillata seeds.

Nakane S1, Tanaka T, Satouchi K, Kobayashi Y, Waku K, Sugiura T.
Author information



Abstract

The umbrella pine Sciadopitys verticillata seeds were found to contain a substantial amount (16.7 nmol/g) of sciadonic acid (all-cis-5,11,14-eicosatrienoic acid)-containing 2-monoacylglycerol, i.e., 2-sciadonoylglycerol (2-eicosa-5',11',14'-trienoylglycerol). Because the structure of 2-sciadonoylglycerol closely resembles that of 2-arachidonoylglycerol, the endogenous natural ligand for the cannabinoid receptor, we examined whether or not 2-sciadonoylglycerol exhibits cannabimimetic activity using NG108-15 neuroblastomaxglioma hybrid cells which express the cannabinoid CB1 receptor. We found that 2-sciadonoylglycerol induces rapid transient elevation of intracellular free Ca2+ concentration in NG108-15 cells through a cannabinoid CBI receptor-dependent mechanism similar to the case of 2-arachidonoylglycerol, yet the activity of 2-sciadonoylglycerol was apparently lower than that of 2-arachidonoylglycerol. The activity of 2-sciadonoylglycerol was detectable from 3-10 nM, reaching a maximum at around 10 microM. To our knowledge, this is the first report showing the occurrence of a cannabimimetic monoacylglycerol in higher plants.



2-sciadonoylglycerol.jpg


There just might be something to this as one seller of these seeds on eBay reports 217 sales! I wouldn't think there would be that much interest in starting rare pine trees from seed.
 
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The Kava plant (Piper methysticum) has been used to prepare a drink in Polynesia that is said to have tranquilizing properties. The active ingredients are the kavalactones found in the roots. One of these compounds binds to the CB1 receptor, yangonin, probably accounting for the tranquilizing effect. While the plant itself is apparently not available, the dried powdered root material is advertised on eCommerce web sites. The FDA warns that excessive use of kava can cause damage to the liver & other organs.

Pharmacol Res. 2012 Aug;66(2):163-9. doi: 10.1016/j.phrs.2012.04.003. Epub 2012 Apr 14.
[h=1]Kavalactones and the endocannabinoid system: the plant-derived yangonin is a novel CB₁ receptor ligand.[/h]Ligresti A1, Villano R, Allar? M, Ujv?ry I, Di Marzo V.
[h=3]Author information[/h]

[h=3]Abstract[/h]To investigate the possible interactions between kavalactone-based molecules and proteins of the endocannabinoid system and provide novel and synthetically accessible structural scaffolds for the design of cannabinoid receptor ligands sharing pharmacological properties with kavapyrones, a preliminary SAR analysis was performed on five commercially available natural kavalactones and nine kavalactone-analogues properly synthesized. These compounds were investigated for assessing their cannabinoid receptor binding affinity and capability of inhibiting the activity of the two major metabolic enzymes of the endocannabinoid system, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). Among the molecules tested, only yangonin exhibited affinity for the human recombinant CB₁ receptor with a K(i)=0.72 μM and selectivity vs. the CB₂ receptor (K(i)>10 μM). None of the compounds exhibited strong inhibitory effects on the two enzymes analyzed. The CB₁ receptor affinity of yangonin suggests that the endocannabinoid system might contribute to the complex human psychopharmacology of the traditional kava drink and the anxiolytic preparations obtained from the kava plant.


Yangonin.jpg
 
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