N&PD Moderators: Skorpio
JWH-015 and JWH-018 legal status
theWorldWithin
Bluelighter
I still would not recomend eye balling any RC, particularly not one that is active in such minute quantities. 1-2 mg, come on, that is like eye balling DOC, insanity. Also I am uncertain about this substances pharmacology, is it a full or partial agonist? If it is a full agonist then eyeballing could be deadly!
fastandbulbous
Bluelight Crew
Eh? Name a full CB1 agonist that has an LD50 that's withing two magnitudes of order of the active dose...
OK it can be very unpleasant, but the whole thing about the cannabinoid system is that it doesn't involve acute toxicity responses
As regards the JWH series, the 1-butyl compound (1-butyl-3-naphthoylindole - don't know it's JWH designation) is much less potent than the 1-pentyl compound; it takes about 5x the amount to get the same effects as the pentyl compound (although it does seem less inclined to cause anxiety).
This sort of goes along the same lines as the 3-alkyl group in THC analogues (the 3-alkyl group in THC being pentyl). I'd imagine that the 1-hexyl will be even more potent, similar to the way synhexyl is more potent than THC. The dimethylheptyl compound, by extension, would only be suitable for psychochemical warfare 
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MattPsy
Bluelighter
Name: N-alkyl || CB1 Ki (nM) +/- x || CB2 Ki (nM) +/- x || CB1:CB2 Ratio
JWH-018 : N-pentyl || CB1 Ki: 9.00 +/- 2.94 || CB2 Ki: 2.94 +/- 2.65 || 3.06
JWH-019 : N-hexyl || CB1 Ki: 9.80 +/- 2.00 || CB2 Ki: 5.55 +/- 2.00 || 1.77
JWH-020 : N-heptyl || CB1 Ki: 128 +/- 17.0 || CB2 Ki: 205 +/- 20.0 || 0.62
The N-hexyl is weaker than the N-pentyl. The N-heptyl is much weaker (tho this is not dimethylheptyl).
Ref: Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding
Drug and Alcohol Dependence 60 (2000) 133–140
This stuff is not like DOB where you CANNOT eyeball it with any semblance of safety. Get it wrong with DOB and you are in for 20+ hours of intense shit-and-piss your pants fear, and possible cardiovascular issues from the intense stimulation.
Get it wrong with these AAIs and the worst you're likely to suffer is incapacitation, so you will climb into bed or a nearby soft object, sleep most of it off, wake up and eat 5 pies consecutively.
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MattPsy said:
One current theory is that the indole pyrrole ring behaves like the 1,1 dimethyl group in DMH-THC compounds and that the ketone oxygen corresponds to the meta hydroxy phenol group in these classical type cannabinoids. so the pentyl and hexyl are approximately equivalent to the 1,1 dimethyl hexyl and 1,1 dimethyl heptyl. I think a lot of the studies on affinities here are hampered by the stickyness of the test compounds, the results gotten are skewed by the material sticking to the glass or plastic containers used in assay.
the most potent ligands in the naphthoyl indole series are those with a bulky hydrophobic group at the end of a 4-5 carbon chain attached to the the nitrogen.
cannabinoids full agonists or not, are pretty non lethal even in massive overdose because the CB receptors are not found in large concentrations in the areas on the brain that deals with basic functions like breathing. That is not to say that these alkyl-naphthoyl indoles should be regarded as in any way safe, they might throw up some dangerous off target interactions or damaging metabolites.
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MurphyClox
Bluelighter
...referring to the last post:
I'm not very familiar with the AAI-compounds of the JWH-series, but Vecktor wrote that
I would conclude that for example a cyclohexyl-pentyl-residue at indol's position 1 would be a winner, therefore.
Vecktor said:
Now some questions:
Is my conclusion correct?
Was such a compound ever described?
-> If yes, under which number?
And what would be the potency in comparison to JWH-018?
What are actually the most potent derivatives of that class of compound? (number provided will be enough)
THX A LOT!
Peace! Murphy
Edit: Or if n-hexyl is inactive, I change my proposal to 1-(cyclohexyl-propyl) maybe...
LuxEtVeritas
Bluelighter
so one would think the hexyl derivatives more potent than the pentyls, but in the assays for whatever reason they are not...
nuke
Bluelighter
More comparative data from related compounds (use the ratio data to get the CB1 affinities):
MattPsy said:
JWH-015 has a K sub i-CB2 of 13.8.+-.4.6 nN/I and a K sub i-CB1:CB2 ratio of 27.5
WIN-55,212-2 has a K sub i CB2 of 0.028+-0.16 nM and a K sub i-CB1/CB2 ratio of 6.75
5-F DELTA B-THO has a K sub i-CB2 of 8.7+-3.5 nM and a K sub i-CB1/CB2 ratio of 6.55
JWH-018 has a K sub i-CB2 of 2.94+-2.65 nM and a K sub i-CB1/CB2 ratio of 3.23
CP-56,667 has a K sub i-CB sub 2 of 23.6+-6.5 nM and a K sub i-CB1/CB 2 ratio of 2.61
L759656 has a K sub i-CB2 of 11.8+-2.5 nM and a K sub i-CB1/CB2 ratio of 414.24
L759633 has a KiCB sub 2 of 6.4+-2.2 nM and a K sub i-CB1/CB2 ratio of 162.97
From this patent: http://www.wikipatents.com/6274635.html
CB2 receptors are supposed to impart an immunomodulatory response, which was the investigation of that patent.
Aeon Psyche
Bluelighter
planckunit
Bluelighter
JWH-019
Aeon Psyche said:
(ref.Influence of the N-1 alkyl chain length of cannabimimetic indoles upon CB1 and CB2 receptor binding
Drug and Alcohol Dependence, Volume 60, Issue 2, 1 August 2000, Pages 133-140)
Aeon Psyche
Bluelighter
Thanks.
I assume it has about the same potency as the other two?
MattPsy
Bluelighter
Murphy: It's the N-((1-methylpiperidinyl)methyl) analogue, the (R) enantiomer I think if you were inclined to do a stereoselective synthesis. Not sure if it has a JWH designation. Hopefully someone useful who is not stoned (rather topically, being an AAI haha) can be a nice person and find the reference for them for me.
I don't think compounds with that N sub mentioned earlier with substitutions on the naphthalene ring, 4-methoxy, 4-fluoro, etc have been made and assayed yet.
When/if they are, if trends follow from the trends in regular N-alkyl AAIs where the naphthalene ring has been modified, these should have affinity Ki's significantly lower than the N-((1-methylpiperidinyl)methyl) analogue ... and when you consider the non-ring-substituted parent compound already has an affinity something like 1/10th that of JWH-018... well, it may be a very strong ligand indeed, 1/20th even.
I say if the trends follow because the basic nitrogen on that piperidinyl ring might change the conformation of the molecule so that the aromatic stacking region is displaced a bit.
However this does not mean the ED50 will be 1/20th the dose of JWH-018, ED50 doesn't scale well with receptor affinity data... especially when you have to predict pharmacokinetics! Still, they will probably be ridiculously potent - this is not really a good thing at this dose level - JWH-018 is hard enough to weigh out by itself coz the dose is so small, so if it's 10% or 5% of that... well, more trouble than it's worth IMO. I would in almost all circumstances recommend that someone not use them.
In fact, it's worth taking note that the extent of epoxidation in the naphthalene ring (which goes through a toxic epoxide intermediate on it's transformation to a diol that can be excreted...) is not well-known as vecktor briefly touched on, as well as his other cautioning of unknown possible other receptor actions.
w.r.t. AAIs mimicking THC/other cannabinoid-type CB ligands, yeah I had noticed that overlay pattern too in 3D.. and when you do an minimizing overlay in Chem3D or Chimera etc. it shows they have the appropriate groups in approximately the right locations - neat! Doesn't mean it's right though, just coz it's conveniently similar. (wow, epic long read, just noticed. sorry 
)
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fastandbulbous
Bluelight Crew
The only reason aromatic hydrocarbons like benzene, naphthalene, anthracene etc undergo epoxidation is to tag them with some polar group to allow the kidneys to filter it out so it can be pissed away. Once you start tagging the aromatic rings with more polar groups, they generally dont hang around long enough to undergo dodgy metabolism via epoxides to the final diol. The carboxyl group situated between the aromatic rings (naphthalene & indole) should be more than adequate for metabolic enzymes to play with, with an eye towards final elimination (eg via conjugation with a variety of things like glutathione, glucuronic acid etc). If not, then things like propiophenone, benzoin etc would be up there with benzene as a carcinogenic risk (there is a related cannabinoid that is purely hydrocarbon in structure - no carboxyl group - it's a methylene group insted - & the indole ring replaced by indane that I think would be very dodgy as the only metabolic route I can think of to introduce a polar group is the dread epoxidation - I wouldn't touch that one with a 10ft shitty stick).
If the JWH cannabinoids even looked slightly like they might be targets for something as dodgy as epoxidation to facilitate excretion, I wouldn't have had anyting to do with them either
fastandbulbous
Bluelight Crew
Oh, that's not good, but then rats have a metabolism that is pretty different to humans in a lot of respects (MPTP does bugger all to them whereas it's instant severe Parkinsons in primates). If they'd found that JWH-015 underwent epoxidation in other primates, then I think I might be on the way to a bout of pretty bad anxiety over the matter (and probably a change of underpants now I've thought about it some more).
I'll comfort myself with the fact that the much higher metabolic rate in rodents makes every aromaric compound more likely to undergo epoxidation than in man in order to facilitate an equally rapid removal from the body. I'm not going near another drop of it until I've done a bit more reading (vecktor, do you have a ref for the paper mentioning the epoxidation of it in rats?)
MattPsy
Bluelighter
Identification of in vitro metabolites of JWH-015, an aminoalkylindole agonist for the peripheral cannabinoid receptor (CB2) by HPLC-MS/MS
Analytical and Bioanalytical Chemistry, Volume 386, Number 5, November 2006 , pp. 1345-1355(11)
Yes FnB, that's why I said "the extent of" - well aware that ketone of the naphthoyl moiety should be (intuitively) the major metabolic route toward making it more polar to excrete it. However on the data available it appears that hydroxylation of the N-alkyl group, N-dealkylation, hydroxylation of the benzene ring in the indole system, and... naphthalene ring hydroxylation through an epoxide intermediate (which then spontaneously rearranges to a hydroxyl, or proceeds to a diol through epoxide hydrolase) are the major metabolic pathways. And mixtures of these, of course.
It's possible that they've made an error and not detected a metabolic product where the ketone has been reduced to an alcohol and then glucuronidated... or that this doesn't happen in rats. It might happen in humans, who knows yet.
fastandbulbous
Bluelight Crew
Well two out of the four metabolic pathways are safe and commonly encountered metabolic routes in primates (hydroxylation of alkyl groups and N-dealkylation) and I believe ring hydroxylation of the indole nucleus is one of the metabolic fates of the simple dialkyltryptamies and nobody has thought to point the finger at DMT, DET etc and call them potential carcinogens.
The bit about conjugation etc was just to illustrate that it's not devoid of polar targets for metabolism (obviously the indolic nitrogen is the other). I just hope that with those three, the extent on any epoxidation of the naphthalene ring is nrgligable/non-existant so asto effectively discount it compared to the background 'noise' from things like acreolins in food etc
Aeon Psyche
Bluelighter
Does anyone know more about JWH-073, JWH-081 & JWH-200? How many of these exist? It sure is fun trying 'em
