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Am-694

Even if it isn't covalently binding, super high affinity for the target isn't that desirable because it can lead to rapid and pronounced tachyphylaxis (i.e. effects will quickly become weaker and weaker with repeated doses). Look at lofentanil for instance, that doesn't bind covalently but it desensitizes opioid receptors just as well as oxymorphazone, which does bind covalently.

That said, I tend to agree with the above statements that the Ki value of 0.08nM for AM-694 is likely erroneous given that the Ki for the 2-methyl analogue AM-2225 is so many times higher! Really you would think the peer review process for granting a patent should be far more stringent than for publishing an article in the scientific literature, considering the legal rights that a patent provides, but unfortunately this does not seem to be the case.
 
So who will dare to test it anyway .. in some micro gram doses ? :)
And i dont think you need extra good scales to make make mix by yourself measure 10 mg dissolve it and spray on herbs wuala.. and you got wanted dosage on exact qty of herb..
 
^No one in their right mind would try it in such a reckless fashion given just the expected possibilities of what may happen...
 
I hope anyone in their right mind would pass on a substance that has a possibility of not releasing the receptor until it's recycled.

Can you imagine an OD? "Oh, don't worry about it, you'll come down in a couple weeks or so, just tough it out. I left you a bottle of 100 valiums, you'll probably need to ration them over upcoming weeks." Haha.
 
Permanently activated receptors (i.e. due to covalently bound ligands) usually get metabolized after several hours, thus extending the actual effect to >12 hours.
The question is on the one hand: What happens to the ligand when the peptidic receptor gets digested? In the worst case it gets released as it was before and goes directly for a new round; but that's just a guess.
On the other hand: What are the physiological effects of such effective and long-term activitation of CB1? Reports of AAI-style cannabinoid overdoses already provide interesting albeit worrying examples... :\

- Murphy
 
That's very interesting... If it were to just get released and then bind again, would the duration be either of these?

A. Until you run out of CB-1 receptors
B. Until your body metabolizes it all during release

Maybe which ever comes first?
 
Well, I would have thought that since the receptor is removed, that the effect would be more like a overdose of Rimonabant (ie. CB inverse agonist/antagonist) once the receptors started to be internalised... so, after the first effect of action.

The stronger fentanyl-style opioids also do this, which is why their withdrawals are so awful and protracted.
Not nice stuff.
 
cegli said:
That's very interesting... If it were to just get released and then bind again, would the duration be either of these?

A. Until you run out of CB-1 receptors
B. Until your body metabolizes it all during release

Maybe which ever comes first?
Click to expand...

I guess one can not 'run out' of receptors, because internalization/digestions always happens with concomitant new biosynthesis. But I can imagine that the anabolic machinery can get 'exhausted' somehow after some time, resulting in a lower receptor density in the long-term. Other regulating mechanism are at work for sure, too.

The action of the ligand will stop sooner or later, because it gets excreted and/or metabolized.


- Murphy
 
Forgive me if this post sounds amateur, but I am not a chemist in any degree. Your discussion has been intriguing, but I think quite a bit of it has gone over my head. If you are so inclined, could you elaborate on the implications of the body's ability to recover from a covalently bonded receptor?

Am I to understand that if one were to take am-694 over an extended period of time that there is a chance that the CB-1 receptors will begin to diminish? So in essence, the longer and the more this chemical is ingested, the likelihood of increasingly adverse consequences can be expected?

Is this the only major theoretical negative effect of am aside from the possibility of it metabolizing into a known toxin?
I realize that these questions should be left out of an advanced drug discussion thread, but I am sure there are others like me who are interested but lack the adequate education in this field to fully grasp what you are saying. After utfse I found that there is relatively no information about the metabolism and toxicity of am-694. So for others who end up on this thread and are in my shoes, I would bet they would also have questions similar to mine.
 
ShaggyKyle said:
So in essence, the longer and the more this chemical is ingested, the likelihood of increasingly adverse consequences can be expected?
Click to expand...
That is true of just about any chemical. However, this has been available from a very well known vendor for awhile now, and rumored at least to be in some smoking blends. If this were acutely toxic I think we would have heard horror stories by now. What I've read from people who've actually tried it seem to suggest that while it is certainly very potent it is not of the hyper-potent nature the published numbers suggest. Whether this is because the numbers are wrong or because the vendor cut it to more managable levels I have no way of knowing. If it is the latter you run the risk of getting unevenly cut product and potentially dosing far higher without actually using more product. I really don't see any good reason to try this, there just seem to many unknowns compared to jwh-whatever.
 
MurphyClox said:
I guess one can not 'run out' of receptors, because internalization/digestions always happens with concomitant new biosynthesis. But I can imagine that the anabolic machinery can get 'exhausted' somehow after some time, resulting in a lower receptor density in the long-term. Other regulating mechanism are at work for sure, too.

The action of the ligand will stop sooner or later, because it gets excreted and/or metabolized.


- Murphy
Click to expand...

Any insight on which pathways may/do stimulate transcription of the CB1 receptor gene? You could probably trace the pathway to its initial receptor and use a correspoding agonist to counteract the effects of receptor diminution.
 
Tried 500mg over the space of 5-6 days, mild headache noted, didn't last as long as it claims to, though the initial rush high of smoking is quite nice, but levels down to a high that isn't so strong.

Using higher amount in a single bowl does not make it subjectively more stronger or more intense, it does not pass a certain point in terms of effect.
 
structural entropy said:
Tried 500mg over the space of 5-6 days, mild headache noted, didn't last as long as it claims to, though the initial rush high of smoking is quite nice, but levels down to a high that isn't so strong.

Using higher amount in a single bowl does not make it subjectively more stronger or more intense, it does not pass a certain point in terms of effect.
Click to expand...
Either this is nowhere nearly as potent as believed or you have a cannabinoid tolerance for the record books.
 
From what little data is available, I'm inclined to hypothesize that AM-694 is a very potent ligand that activates the CB1 receptor very weakly. This would simultaneously explain the high Ki reported in the patent, the apparent activity at doses significantly below JWH-018, and the rapid saturation of effects with increasing dosages.

Perhaps one willing to risk sacrificing themselves to science could test this idea by experimenting with co-administration of JWH-018 and AM-694. Presumably were the above true, AM-694 might make it much harder to overdose the JWH-018, which could be desirable. Moreover, I suspect that non-THC cannabinoids in Cannabis act similarly to moderate the effect of THC.

OTOH, I'm interested in suggestion that a pico-molar Ki implies irreversible binding. Not being a biochemist, I'm not aware of any particular rule-of-thumb to use in this instance. To me, pico-molar affinity sounds pretty darn potent but still quite reversible; however, as Ki values get real small, I imagine the measurement errors increase without bound. Perhaps then a pico-molar Ki might be observed when the true Ki is like 10^-18 M (!).

Also, does anyone here have any knowledge of characteristic timescales for (1) internalization of activated CB receptors; (2) replenishment of irreversibly block CB receptors. I recall that Botulism poisoning takes on the order of months to recover from. :/
 
FryingSquirrel - Smoked weed for only 3 years, with dabbling in synthetic cannabinoids over the past 5-6 months. My cannabinoid tolerance isn't that high.

I do not think ki values are such good estimates to measure potency, as I still find good old marijuana to give me the best buzz out of all of them.
 
structural entropy said:
FryingSquirrel - Smoked weed for only 3 years, with dabbling in synthetic cannabinoids over the past 5-6 months. My cannabinoid tolerance isn't that high.

I do not think ki values are such good estimates to measure potency, as I still find good old marijuana to give me the best buzz out of all of them.
Click to expand...

IME, physiological tolerance to cannabinoids (THC and others) builds and falls-off rapidly over a few days to a couple weeks or so. Your lifetime experience may affect your psychological sensitivity to the experience, but that's another story.

Did you notice a rapid ramp up in tolerance to AM-694 (or other cannabinoids) that coincided with your first few uses of AM-694? With some users reporting activity at ~1 mg, it would seem to me that consuming 500mg over 5-6 days indicates either a preexisting tolerance or a rapid build-up of tolerance.

Can you comment on any differences in effects and/or tolerance with other cannabinoids (or weed) after you consumed 500mg of AM-694?
 
Mild headache, some diarrhea. I'm lethargic most of the time with or without weed or related cannabinoids, so that's not much of a difference.

I had been smoking weed at the same time as smoking the am-694, but when compared against something like weed, weed clearly wins out. It is somewhat long lived, but it does not 'feel' as clean as jwh-073, the effect compared to 073 is slightly stronger, but not as relaxing. I find myself needing to redose artificial cannabinoids after 20-30 minutes, just to feel the initial rush again, rather than a point on AM-694's effect being 'over' at that point.

All in all, it's quite similar to others in the jwh series, I've done 018, 073, and 200. There was no overwhelming panic at higher dosages of am-694 as is common with 018.

Somehow I do not think the AAI chemical structure is optimal when it comes to lasting more than an hour in primary effect.
 
Well shit, the only reason to try this I can see was being a cheap bastard. If it isn't all that potent, fuck it, why risk that the speculation about toxicity and receptor damage (even if that apears less likely) is correct? I agree plain old herb is the best, but my probation officer takes a different veiw. I'll be sticking to JWH.
 
It may be more potent with the right pipe. I only use a glass piece with a screen, no 'oil burners'. In fact I've never used an oil burner and I would be curious if I would be able to get more of the good stuff through that route.

But yeah... compared to jwh-073, not much to write home about.

Plus you can taste the iodine when smoked. It has a very distinct metallic taste.
 
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I have gotten better results with a meth pipe type thing compared to putting it in a regular pipe. Noticed this more with 073 than 018, but that's probably just due to the difference in potency.
 
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