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anandamine transporter(re-uptake) inhibitors

A

allthegoodjwh's

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Joined
Aug 8, 2012
Messages
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anybody think these can hold a candle to other classes of synthetic cannabinoids (especially the ones with very high cb1 affinities) ?

what about when combined with an FAAH (Fatty acid amide hydrolase) inhibitor, to prevent the breakdown of all the Anandamine floating around in the synapse? (also because most of the chemcials ive come across are both FAAH inhibitors and anandamine re-uptake inhibitors)

what about in combination with a CB1 agonist?

would like to have a discussion on this topic, also if anyone (or knows anyone) that has tried one of these

some of the ones i found were

Arvanil
Potent CB1 and TRPV1 agonist. Also anandamide transport inhibitor
(interesting as it acts on both CB1 and the anandamine transporter)

as well as this one too

NADA
Endogenous CB1 agonist. Also vanilloid agonist and inhibitor of FAAH and AMT

LY 2183240
Novel, potent anandamide uptake inhibitor. Inhibits FAAH

O-2093
Inhibitor of anandamide uptake

OMDM-2
Potent inhibitor of anandamide uptake
 
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I was unaware there was such a thing as an anandamide transporter.

URB-597, a putative FAAH inhibitor, has had some human trials but the end result it it's useless. One guy even managed to blow his kidneys away from ingesting shit contaminated with cadmium.

Not sure how useful these compounds would be, given most people probably want CB1 partial agonism.
 
well i was going through new RC's and found a new class
some were called inhibitors of the AET
or AEA (Anandamine) membrane transporter

my thoughts were that an AET-inhibitor
combined with an FAAH inhibitor would cause massive extracellular concentrations of anandamine (and the FAAH inhibitor would prevent it from being immediately broken down)

my question is do either you you know the affinity of anandamine for the CB1 and CB2 receptors
as if it is of reasonable potency than it is possible for these to become a new recreational form of synthetic cannabinoids

also it would help circumvent new synthetic cannabis bans as CB1 agonists are past their prime and are begging to get too dangerous for my tastes

i was curious as to if anyone has experimented with any of the listed AET-inhibitors or (other)
as i know this will become mainstream if there's the tiniest potential for recreational damage and it avoids all current drug laws in the US/world

my quesiton is what would be the effects (if any) of these substances (i would imagine it would be a natural THC high very close if not identical) instead of the balls to the wall pcp dissociative trips from CB1 full agonists

and if there are any fucked up side effects associated with them (such as the gentlemen blowing his kidneys out on URB-597)
i would imagine it would be a completely safe (maybe not the most recreational) but it should have a high tolerability as it acts through an increase in anandamine versus high affinity CB1 modulation
 
Acetaminophen is metabolized in to a cannabinoid reuptake inhibitor, to put it in to perspective.
 
actually it is an FAAH inhibitor


"AM404 was originally reported to be an endogenous cannabinoid reuptake inhibitor, preventing the transport of anandamide and other related compounds back from the synaptic cleft, much in the same way that common SSRI antidepressants prevent the reuptake of serotonin. Recent work on the mechanism of AM404 has suggested that the inhibition of fatty acid amide hydrolase (FAAH) by AM404 is likely responsible for all of its attributed "reuptake" properties, since intracellular FAAH hydrolysis of anandamide changes the intra/extracellular anandamide equilibrium" - wikipedia page on AM-404

its available as an RC i was wondering when it would show up as it has cannabinoid activity and isnt part of any ban
also drug testing for it would be quite difficult as acetaminophen has AM-404 as it is a pro-drug of it
and fucking everyone takes tylonol and would have Am-404 in thier piss (maybe not a recreational dose of it but it is still present and would make a pretty fucked up cut-off leval for that test)

also im interested in the effects of Am-404 by itself as to achive a recreational dose of it from acetaminophen youll lose your liver as well so in *free form* it may yield some psychoactive effects

like i said before a combination of an AET-inhibitor and a strong FAAH inhibitor
could make a novel reacreational drug that is much closer to spice than a trip your balls off cannabinoid CB1 agonist that borders in the Um in potency
i just wish there were some bluelighters who have tried these by themselves or in combination and could report on the effects as they are pretty damn new compounds with the exception of AM-404
 
Tylenol doesn't contain AM-404. It's a pro-drug for it, but not in the way that codeine is a pro-drug for morphine. It's not something like simple demethylation, but rather conjugation that yields that active metabolite.
 
sekio said:
I was unaware there was such a thing as an anandamide transporter.

URB-597, a putative FAAH inhibitor, has had some human trials but the end result it it's useless. One guy even managed to blow his kidneys away from ingesting shit contaminated with cadmium.

Not sure how useful these compounds would be, given most people probably want CB1 partial agonism.
Click to expand...

There does seem to be some active mechanism of endocannabinoid uptake, but the transporter is still unknown as far as I can tell, and unfortunately some (all?) of the inhibitors also inhibit release so they do seem kind of pointless.

Evidence for bidirectional endocannabinoid transport across cell membranes.
http://www.ncbi.nlm.nih.gov/pubmed/22879589


allthegoodjwh's said:
what about in combination with a CB1 agonist?
Click to expand...

Again not sure how useful compounds with this combo will be, but here's a weak one, OMDM-6

Novel selective and metabolically stable inhibitors of anandamide cellular uptake.
http://www.ncbi.nlm.nih.gov/pubmed/12732359
 
allthegoodjwh's said:
what about when combined with an FAAH (Fatty acid amide hydrolase) inhibitor, to prevent the breakdown of all the Anandamine floating around in the synapse? (also because most of the chemcials ive come across are both FAAH inhibitors and anandamine re-uptake inhibitors)
Click to expand...

Sounds like anandamide hydrolysis occurs mostly intracellularly, so I don't see that there'd be much difference, practically, between a FAAH or transport inhibitor. This paper (it's a bit old and I just started reading) says, "In 1993, it was shown that anandamide was readily taken up by cells in culture and broken down into arachidonic acid and ethanolamine by an amidase, the FAAH (6). By breaking down anandamide, FAAH maintains an inward gradient that drives anandamide influx." So whichever way you do it the end result is an increase in synaptic anandamide concentrations.

Also, the effect of direct agonists is not necessarily anything like the effect of agonism by endogenous agonists. I don't know about CB receptors, but with 5-HT2A, the response to psychedelics is very different from the response to 5-HT.
 
I was reading up more on what we know about anandamide transport and came across this:

A catalytically silent FAAH-1 variant drives anandamide transport in neurons.
http://www.ncbi.nlm.nih.gov/pubmed/22101642

Abstract
The endocannabinoid anandamide is removed from the synaptic space by a selective transport system, expressed in neurons and astrocytes, that remains molecularly uncharacterized. Here we describe a partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH-like anandamide transporter (FLAT), that lacked amidase activity but bound anandamide with low micromolar affinity and facilitated its translocation into cells. Known anandamide transport inhibitors, such as AM404 and OMDM-1, blocked these effects. We also identified a competitive antagonist of the interaction of anandamide with FLAT, the phthalazine derivative ARN272, that prevented anandamide internalization in vitro, interrupted anandamide deactivation in vivo and exerted profound analgesic effects in rodent models of nociceptive and inflammatory pain, which were mediated by CB(1) cannabinoid receptors. The results identify FLAT as a critical molecular component of anandamide transport in neural cells and a potential target for therapeutic drugs.
Click to expand...

I guess I take back what I said before, that part in bold does sound promising.
 
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The pharmacology looks nice, the compound not so much:
fJZaq.png


5 rings, a hydroxyphenylaminopthalazine moiety, a PABA group, and aniline...

I think these compounds have a bit further to go before I'd feel comfortable ingesting them. They look like lead compounds, to be frank...
 
i figure eventually we will see the rise of releasing agents not unlike amphetamine for this transporter, id be interested to see what effects those had
 
Be careful of just inhibiting part of the arachidonic acid cascade for the sake of prolonging the duration of action of endocannabinoids or exogenous CB1 specific agonists. Some of the cannabinoid analogues have very long duractions of action because their total clearance (CLT) and Volume of Distribution (VD) are so low and so high, respectively (not because of half-life (t1/2)). One of them that came out around the same time as HU-210 had a duration of action of over 6 days (I believe it is JWH-018 but I'll leave you to look it up if you're interested.)

Now as someone who pretty much stopped smoking pot in the 80s because of the tachycardia and paranoia that it started to give me, and has smoked maybe a dozen times since then, I did find HU-210 had all the good aspects IME of Δ9 THC, without the bad; but I never did it more than a few times. Mainly, my concerns are related to things like the issues from problems suspected to have resulted from some of the cyclooxygenase inhibitors, as this pathway is intimately involved with inflammation and muscle contractions (Prostaglandins PGE2, PGF2, etc.) and our large gaps (or at least mine) in the understanding of the functions of all parts (or at least many of the lesser ones) of this system. In addition, the problems that many of the MAOA Inhibitors caused over the years in combinations with other drugs. Most of the enzymes involved in Phase I Biotransformation affect different substrates, some likely unknown, and their functions give me pause with ingesting these combinations without data, but I have no double-blind or anecdotal data from problems possibly associated with this that state or any specific ideas about what those would be.

MobiusDick
 
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mobius dick i have heard about the chemical you speack of, i do not believe it to be jwh-018 only because it was so popular in blends (especially in late 2010) that the media would have been covering 1000's of er visits from adverse effects
my friends recieved a chem belived to be hu-210 it was 600-800$ for very few milligrams and of ridiculous potency we basically became stuck, where i was walking in place
(if we closed our eyes and walked we wouldn't go anywhere) the trips i got from that were increadibly dissociative where one "hit" from the chem felt like very good pcp and i was falling through the floor and someone pressed pause on the dvr on my life
the duration was easily 6+ hours for peak effectcs if i remeber correctly but it was years ago (before spice became popular and i think also before or right as hu-210 was scheduled)
great chem tho id repeat it but use a scale as we eyeballed it and it is far too potent (very forgiving though) NOT LIKE 018 FUCK EYEBALLING THAT right up there with am-2201 as as the most anxiogenic drug ever experienced and ive done trips like 3+ deylsum and robotussin bottles at once and hit sigma

also to reply to what skillet said, yes that was a concern of mine that the cb1 may behave like 5ht2a and not do shit unless its agonized by a non-endogenous chemical but i also remember hearing about oleamine being in some spice blends and its an endogenous cb1 FULL agonist as well as gabaA agonist and correct me if im wrong but it produced psychoactive effects
anadamine is released during child birth to exert analgestic effects and help the mother "froget about the birth" so she will repeat it other wise she will be like fuck that shit
if thats true its interesting as its a natural "erase button of the brain"
kind of like kappa-opioid agonists
or ketamine used to "froget addiction"
by i think modulating downstream glutamate currents
and resseting them in the nucleus accumbends for one
idk im rambling... prescription adhd drugs
but yeah its possible anadamine could exert psychoactive effects
i think the reason it doesnt naturally is because its
either and/or
cannot reach a high enough concentration (low affinity?)
broken down to fast - like oxytocin

one of the reasons i started this was to inquire if anyone had ingested these compound or knew or any in vitro studies
because either a aet-inhibitor/faah inhibitor combo
or if possible aet-releasing agent \
could prove a novel cannabinoid drug class that could not only have recreational potential but possible medical potential as
certail FAAH inhibitors have anti-depressant, anxiolytic and analgestic effects in studies (lemme find them its been ahwile)
 
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From all classes of pharmacological action reuptake inhibtors are my favorite.

Why? Because in opposite to agonists they do not artificially create randomly signals in the brain that not already were there before (in a weaker form). This is why Dopamine Reuptake inhibitors are by far better for improving concentrating than Releasing Agents, which create a lot actually needless (but fun ;) signals no matter what.

The same consideration should apply to all other Reuptake Inhibitors just as well.
 
I'll just add a tiny blurb before engaging this thread properly...

sekio said:
I was unaware there was such a thing as an anandamide transporter.
Click to expand...

Well, anandamide actually has very vigorous reuptake, as because it is so lipophilic, such is necessary for cannabinoid mediated transmission to be well regulated. It makes sense that there could be effective pharmacological agents for this target.

ebola
 
i will be receiving a sample of LY-2183240 in a few weeks. does anyone have any more information on this class of chemical?
 
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