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CB2 selective agonist

T

Timothy Leary

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Dec 5, 2009
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This is probably the last question that would be asked here, but I am looking for a synthetic cannabanoid that is pretty available (you know the ones, 250, 200, 81, 18, 91 and some of the weird sr and rcs compounds) and has a high specificity for the nonpschoactive CB2 over over the CB1 receptors. The CB1 are noninflammatory and antialzhiemers effect inducing, I know a person who's family member's memory has been in rapid decline, and up until this point that person has had trouble getting a hold of more 'conventional' agonists despite much effort.
 
I have a suspicion CB2 activation may be anxiogenic. JWH-073 is commonly preferred over JWH-018, and it has a Ki of 8.9 nM at CB1 and 38 at CB2, whereas JWH-018 has a Ki of 9 nM at CB1 and 3 nM at CB2. That is, the main difference between JWH-018 and JWH-073 is that the former has over ten times the CB2 affinity. And the major difference reported by the users is that JWH-018 is much more anxiogenic than JWH-073.

Further, if CB2 activation were truly "non-psychoactive", JWH-073 would be reported as (very slightly) more potent than JWH-018, and the reverse is true. The idea that CB2 is non-psychoactive seems to have been perpetrated in the medical literature almost as if by a long game of telephone, because the data on these agonists in humans is basically nonexistent.

This isn't the first time some cannabinoids have been incorrectly declared "non-psychoactive" -- cannabidiol is almost always referred to as such, despite an abundance of literature showing the presence of antipsychotic and anxiolytic effect, and the fact that THC + CBD has been repeatedly demonstrated as producing markedly different effects than THC alone. CBD is an agonist at 5-ht1a with some residual affinity for 5-ht2a (yes really).
 
I thought CB2 was only expressed in peripheral tissue, though looking at wiki it says it's expressed in the brain but only in microglial cells, not neurons. Still, activation of CB2 could be indirectly psychoactive, I guess. Also there seem to be other cannabinoid receptors that could be involved...

I always assumed that when people refer to CBD as non-psychoactive they mean it's not psychoactive in the same way as THC. It would be absurd to say it's not psychoactive at all. I wonder how it binds to 5-HT1A, btw, it's hardly a typical 5-HT receptor ligand. I guess it binds to a different site.
 
I have heard both figures, usualy only the binding affinities for jwh-018 show a relatively equal cb1 and cb2 effect, but text often says it has a "4 fold" preference for the former.

Speaking of cannabidiol I would really like to find a strain of MJ that produces an extremely low THC content, but a very high CBD content. I never really liked cannabis as it provoked some very strange and varied reactions, I would become totally detached sometimes, incomprehensible others, and paranoid with (probably psychosomatic) hypertension in other cases. I think it has to do with the THC/CBD ratio, schitzophrenia, pschosis and other disorders are very common in my family.

Are there any strains that produce said low THC/CBD ratios, I want something that is like ditch-weed or worse based upon perceived intoxication, I would really prefer for it to be 'psychoactive' in the sense of resembling THC.
 
Good question, I get the same type of reaction to cannabis and have wondered about the therapeutic properties of CBD too. I've heard that the relative CBD content increases if it's harvested past the optimum time, presumably due to degradation of the THC. So maybe you could degrade some cannabis/cannabis extract by exposure to light? It seems that THC degrades to CBN, but I can't find anything about the stability of CBD...

http://www.erowid.org/plants/cannabis/references/journal/cannabis_degradation1.shtml
 
JWH-133 is highly selective for CB2... whether its readily available or not I'm not sure, but that's one to look for.
 
I don't know if this helps you but:

Echinacea is a CB2 agonist.

"Alkylamides from Echinacea are a new class of Cannabinomimetics" (2006)
J. Biol. Chem.
 
Echinacea, Really? I have always been interested in non cannabis derived chemicals that effect the cannabanoid receptors, But I always thought that it was a kind of salvia divinorum situation, one really strange fluke of a chemical that is only in one or two species. Are there any species that produce other cannabis like chemicals (barring the olivetol lichens)

Imagine how many awesome or strange drugs exist that have never been discovered or have gone extinct, perhaps in the Triassic there was a endocyte claviceps fungus that grew on some reed grass which produced LSD, but is now extinct. It is almost poetic to think of all the possibilities, I mean what if the THC sythase protein was never produced through mutation, or if salvia divinorum had suffered the very possible fate of falling prey to its own sterility.


Its interesting to hear of someone who has the same reaction to cannabis. It is always different for me. It is like I am taking a different drug every time, It might be similar with the same batch, but even then it is unpredictable. I tend to be very sensitive to dose, and my reaction is usually a very dramatic version of my friends, I just get completely unintelligible sometimes, but I noticed muscle twitches are common with me, and on some occasions completely passing into a nitrous oxide like anesthesia for a second or two..
 
skillet said:
I thought CB2 was only expressed in peripheral tissue, though looking at wiki it says it's expressed in the brain but only in microglial cells, not neurons. Still, activation of CB2 could be indirectly psychoactive, I guess. Also there seem to be other cannabinoid receptors that could be involved...
Click to expand...

There is decent expression on neuronal cells in the cerebral cortex and hippocampus.
 
Hammilton said:
Are you sure about those numbers? If I remember right, 073 has something like 4x higher affinity at CB2 than CB1 (http://www.ncbi.nlm.nih.gov/pubmed/10940540), not almost 5x lower affinity... hmm... can't open it for some reason. maybe i can find it in my other home..
Click to expand...

I think whoever wrote the wikipedia article mistakenly associated a higher Ki with a higher affinity.
 
I know I have that article but I can't seem to find it. Maybe I didn't save it?? Oh well, that's a pretty common mistake.
 
JWH-120 is very selective towards CB2. CB1 affinity is 1054nM and the CB2 affinity is 6.1nM so the selectivity of CB2 over CB1 is 173.

JWH-151 is also selective of CB2. CB1 affinity >10,000nM and the CB2 affinity is 30nM so the ratio is >333 but it would be less potent.

Huffman JW, Zengin G, Wu MJ, Lu J, Hynd G, Bushell K, Thompson AL, Bushell S,
Tartal C, Hurst DP, Reggio PH, Selley DE, Cassidy MP, Wiley JL, Martin BR.
"Structure-activity relationships for 1-alkyl-3-(1-naphthoyl)indoles at the
cannabinoid CB(1) and CB(2) receptors: steric and electronic effects of naphthoyl
substituents. New highly selective CB(2) receptor agonists." Bioorg Med Chem. 2005
Jan 3;13(1):89-112. PubMed PMID: 15582455.
Click to expand...
 
Yeah but 120 and 151 are nowhere to be found on the RC market (surprise surprise) If they were I would already be dealing them mixed into prune juice behind nursing homes :)
 
I believe perittotenine, from New Zealand liverwort is mostly CB2-selective.

http://en.wikipedia.org/wiki/Perrottetinene

However I still think that CB2 activation will cause significant, noticeable psychological effects, which may or may not include anxiogenesis. I wouldn't secretly dose anyone with a CB2-agonist under any circumstances -- it puts other people at serious risk. Further I'd suggest avoiding the naphthoyl-compounds in favor of AM-694, JWH-250, SR-xx, etc.
 
Suggestions for CB2-selective agonists of the AAI-family (in parentheses the Ki-values for CB1 resp. CB1 in nM):

JWH-004: 1-n-hexyl-2-methyl-3-(1-naphthoyl)indole (48±13; 4.0±1.5)
JWH-015: 1-n-propyl-2-methyl-3-(1-naphthoyl)indole (164±22; 13.8±4.6)
JWH-046: 1-n-propyl-2-methyl-3-(7-methyl-1-naphthoyl)indole (343±38; 16±5)
JWH-047: 1-n-butyl-2-methyl-3-(7-methyl-1-naphthoyl)indole (59±3; 0.9)
JWH-094: 1-n-propyl-2-methyl-3-(4-methoxy-1-naphthoyl)indole (476±67; 97±3)
JWH-120: 1-n-propyl-3-(4-methyl-1-naphthoyl)indole (1054±31; 6.1±0.7)
JWH-151: 1-n-propyl-2-methyl-3-(6-methoxy-1-naphthoyl)indole (>10,000; 30±1.1)

...enough for the moment. The list goes on and on...

JWH-018 is roughly 3 times more CB2-selective.


Peace! - Murphy
 
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