N&PD Moderators: Skorpio
Am-694
summerdaze
Greenlighter
http://en.wikipedia.org/wiki/AM-694
would this cannabinoid even be worth researching?
i have a vendor who supplies it, and im wondering if i should even bother.
so anyone have any comments, ideas?
Limpet_Chicken
Bluelighter
It will be a highly potent cannabinoid, active almost without a doubt in vivo, 0.08 nm affinity for CB1, which compared to THC, IIRC, and this is not an exact figure, has a binding affinity for CB1 of 30-40something nm.
I'm unhappy about potential fluoroalkyl business coming off post ingestion though, that said, the dose could well be so small as to present no effect,
http://bluelight.ru/vb/showthread.php?t=488959 See this thread.
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summerdaze
Greenlighter
what do you think a good dose would be?
and i hear all this talk about the toxicity..
i mean what is your opinion?
summerdaze
Greenlighter
are they talking dosages in the micrograms? or would it be in the range of 1-2mg?
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you are dangerously ignorant
summerdaze
Greenlighter
how am i ignorant?
everybody has to test out a chemical at some point in time, whether it is hu-210 or jwh-018.
i have talked to my supplier, and they have done a lot of testing on AM.. according to them it is not toxic, and they are an actual chemical supplier/lab.
i am just curious as to how potent it would truly be IF someone at some point in time decided to test it.
but most people testing out a new compound realise what picomolar affinity compared to single digit nanomolar affinity in other known similar agonists means and can work out a sensible initial dose on that basis without having to ask dumb questions.
they also might ask themselves the question, just why does this substance have such high apparent affinity, and why is it just so goddamm good at preventing 3H CP 55940 and 3H win 55212-2 from binding to CB1R
They might also want to know what the metabolites are, to be absoluely sure it doesn't metabolise to anything nasty
summerdaze
Greenlighter
listen you obviously know what your talking about no doubt about it, i do not know what any of that is to be honest.. which is why i came here to ask.
could you please explain to me exactly what dose would be needed, and also if this really is dangerous and shouldnt be messed with.
sorry for all the questions, i am just really curious since all the bans have gone through in my state and i would like to test out some new RC's.
MattPsy
Bluelighter
"i do not know what any of that is to be honest"
thus proving vecktor's assertion correct.
what vecktor said: "why is it just so goddamm good at preventing 3H CP 55940 and 3H win 55212-2 from binding to CB1R"
I'll give you a little hint. perhaps it binds so strongly, that it never lets go. that is, until your body recycles the receptor.
I'd suggest not playing with this compound or indeed any others you do not fully understand the actions of or implications of parts of it's structure and the resulting pharmacology of such.
summerdaze
Greenlighter
i will be following your advice.. thanks.
Limpet_Chicken
Bluelighter
Vecktor, what are the stats for binding inhibition of the tritiated CP compound at CB1?
Am I to be thinking that AM-694 might be N-desalkylating in vivo and re-alkylating (alkylating the user, that is) ? in a manner similar to say, oxymorphazone or those irreversible fluroalkyl FAAH inhibitors? what is the duration of action of this compound, in vivo in animal studies if they have been done.
I suppose that would be marginally better than a krebs cycle fucking agent ala fluoroacetate if any fluoroalkyl metabolite never got a chance to enter the krebs cycle and just irreversibly buggered cannabinoid receptors, at least in terms of survivability.
Summerdaze, there are two potential risks I see with AM-694, the first, and most concerning is that the fluoropentyl side chain may come, this metabolic fate is known for JWH-018 which on the sidechain, as opposed to the napthoyl moiety, which the AM compound does not share, undergoes both hydroxylation and elimination, some of the fluoroalcohols (as discussed in the other thread) are really, really nasty toxins, and fluoroacetic acid (aka 1080, a particularly insidious pesticide) is metabolised to fluorocitric acid, which enters the krebs cycle of cellular respiration, and basically sticking a spanner in the works, which in laymans terms 'kills you'
The other concern of mine a directly free fluoroalkyl species, which if its anything like the other haloalkyls, will prove an alkylating reagent, adding a pentyl group to random places on proteins, such as receptors, enzymes, and if its the right size and shape, a DNA intercalator (which means that it bonds between the two DNA strands, acting in a sense, like a broken tooth on a zipper would do, forming a barrier for the bodys polymerase enzymes, which expect certain substrates, not big, bulky alkylated bits and pieces, and thus acting as mutagens and are usually carcinogenic)
Also alkylating ones receptors in that manner would result in a covalently bonded receptor-ligand complex, I.E irreversible activation of CB1 at first, until CB becomes desensitised, and internalises (has to be taken out of service, pulled into the cell and destroyed, followed by de novo synthesis and trafficking of new receptors)
I am sure the assay Makriyannis and Deng ran was worked using hot CP-55940, check the patent and this gave the wiki quoted figure of a Ki of 0.08 nM ! there is other data on it somewhere else which I will find.
MurphyClox
Bluelighter
The "F" presumably slows down metabolism at the alkyl chain. It also increases lipophilicity.
The "I" emulates the second ring of the former naphthyl-system, thus increasing lipophilicity and steric demand without bearing the suspected toxicity of the naphthoyl-moiety.
And as usual, the easiest answer to "Why does this compound in particular fits resp. activates receptor XYZ so much better than its derivatives" is: Because it just fits so damn good.
I would be VERY careful with assaying this compound! The better known AAIs are already very potent and anxiety, panic attacks and sheer paranoia were reported repeatedly upon overdosing. With such a potent fucker, how could one measure out properly the correct dose?! ![:\](https://bluelight.org/xf/BL_Images/Orig_Emoji/wrygrin.gif "wry grin :\")
DO NOT TRY THIS AT HOME, KIDS!
- Murphy
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the affinity is in vitro, therefore no metabolism. there is no public in vivo data.
yes and other bulky lipophilics work also
that is a simplistic answer and doesn't withstand even cursory scrutiny
the question is why is it such an outlier,
quick energy calculations show, as entropy and binding energy and affinity are all related, a suspiciously huge increase in binding energy for the CB1R-AM694 complex compared to estimates for the related compounds, a few extra van der wals or a H bond is just not enough. which leads to the conclusion either the numbers are wrong: either the Ki or the energy calculations, or there is something more to this.
it is also highly suspicious that an achiral molecule like this has higher alleged affinity than the chiral benzopyran cannabinoids and the ABD non classical cannabinoids.
picomolar affinity is pretty rare and even rarer in simple achiral molecules,
I would be VERY careful with assaying this compound! The better known AAIs are already very potent and amxiety, panic attacks and sheer paranoia were reported repeatedly upon overdosing. With such a potent fucker, how could one measure out properly the correct dose?!
DO NOT TRY THIS AT HOME, KIDS!
- Murphy
MurphyClox
Bluelighter
Yes yes, I admit, my choice of words was of course a bit oversimplifying...
With respect to the Ki-value of 0.08 nM, well, I doubt it somehow. It's more a gut-feeling, but looking for example at the closely related compounds AM-2225 (that is AM-694 + a methyl-group at the indole's pos. 2) with a Ki at CB1 of 5.57 nM (80 times higher!), or AM-679 (i.e. AM-694 but with a H for the F) with a Ki at CB1 of 13.5 nM, I doubt that picomolar affinity is for real.
Apart from the differing Ki-values for close relatives, I doubt information from current patents in general, if is not backed up by a reliable source. Patents are notoriously badly phrased and often cryptically written. Nobody checked these values in any way, and usually nobody puts them in doubt if they may vary so drastically from other measured values.
What does a single fluorine-atom offer in contrast to a hydrogen in the same place? Suggestions:
1. Metabolic stability, but as was mentioned by Vecktor, this is irrelevant when talking about in vitro data.
2. The van der Waals-radius of H vs. F are quite similar; fluorine's is just ~20% larger. As hydrophobic residues in that position are well tolerated within a consirable range of substitutions (propyl, butyl, pentyl, hexyl; all straight or branched; morpholino-ethyl; piperidinylmethyl, ...) without changing CB1-affinity this drastically, I don't think that the difference in sizes is the deciding parameter.
3. Different hydrophobicity maybe? Substituting a hydrogen for a fluorine leads to an increase in overall hydrophobicity, but when substituting just a single proton in a C5-chain, the difference is quite small. I think this can be disregarded as deciding reason, too.
4. In contrast to a hydrogen, fluorine can act as hydrogen-bond acceptor. Maybe this makes the difference. What are the proposed amino acids that surround the hydrophobic binding pocket (ie. the one where the N-alkyl residue of the AAIs goes)? Mayb interaction occurs not with a amino acid sidechain but with the backbone, thus forming a hydrogen bond of the type N-H•••F, which is indeed possible...
Again, I must emphasize that I doubt the 0.08 nM-value somehow...
Peace! - Murphy
Edit: I'd like to add one point to the short list above:
5. Fluorine is capable of providing so-called orthogonal multipolar interactions with target proteins. These should not be confused with hydrogen bonds (atom distances are too large). This can indeed make a difference between Ki-values of 1-2 orders of magnitude. An example was published in Org Biomol Chem 2006, 4, pp.2364 – 2375, where thrombin inhibitors were studied. The Ki-values of one compound vs. a derivative where a proton was changed for a fluorine got down from 310 nM to 57 nM.
I think that this property is unique for fluorine and not shared by related atoms (ie. halogens); for example with a chlorine-substituent in the same position the Ki was just about 190 nM. Could this be the answer?
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MurphyClox
Bluelighter
Indeed!!!
Limpet_Chicken
Bluelighter
And if smoked, who knows what kind of fluorinated pyrolytic crap might get churned out when it gets torched with a lighter coated on a mixture of random herbs.
Dresden
Bluelighter
Besides the obvious similarity to the jwh's, which are known to be active by me personally and many others, my opinion was based on the observation that the gamma C from the aromatic ring is still sp2 hybridized, a known requirement for many psychoactive thc-mimetics.
I gleaned that bit of information from an old tome in the science library once.
I still don't think the F and I are desirable, but that is only my opinion.
