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N&PD Moderators: Skorpio | thegreenhand
Rimonabant (Marijuana Blocker)
- Thread starter NeoLime
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Holy_cow
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See US Patent US2007060638.
Tchort
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The purpose of the experiment was to monitor the effects of different hallucinogens on human subjects (in this case addicts inside Lexington). It is a coincidence that years later Ibogaine was found by some to treat addiction (plus the CIA experiment was done on men who had already been detoxed; Ibogaine only works if it is taken during active addiction).
I don’t mean any problems by reviving a 10+ year old thread but I’m REALLY in need of advice. Which drugs actually block the inactivation or reuptake of anandamide and 2AG?
FAAH inhibitors essentially are to endocannabinoids what MAOI's are to monoamine neurotransmitters.
https://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase
Unfortunately, it looks like *a lot* of basic research needs to be done on this class of drugs before they can be safely ingested by human beings: In 2016, a Phase I human trial of the compound BIA 10-2474 resulted in one person dying and several others suffering lasting brain damage, likely due to its unintended action on other enzymes.
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Are people aware that this drug was removed from many markets because it markedly increases the suicide rates in those prescribed it. The CB1 receptor - be it paracetamol or Spice??™, it's not to be played with too lightly. Oh, and while I'm here, that Greek dude who is the worlds leading chemist on CB1 ligands, swapping that funky 1,1-dimethyl at the head of the long alkyl chain with a cyclobutane ring, affinity goes up (i.e. down) by 2 orders of magnitude so that 5L scale glassware setup? Throw it away and get a James Bond-like microscale setup in a carry case. BF3 etherate is not good.
sekio
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I thought it was well-known these days. And it makes sense logically, cannabinoid activity obviously is involved in a crapload of stuff in the body: the psychological state of eudaimonia or perhaps contentment, in addition to blood pressure, heart rate, sleep architecture, hunger, sexual effects, effects on short term memory, inflammatory effects, immune modulation, etc. etc. Such reductionistic application of a CB1 agonist seems foolish if it's in the pursuit of just one of these effects in ignorance of the rest.
So the only real application of such drugs is either research (binding assays) or acute treatment of full-agonist CBxR ligands, for instance, JWH compounds and their friends, all the way to the amino-acid-alkylindole "alphabet soup" generation of Pfizer cannabinoids that seem popular now.
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Male tobacco smokers have brain-wide reduction of CB1 receptors
This explains...
-Studies finding greater anxiety and depression in smokers (probably increased suicide/suicidality too)
-Some physical detriments and chances of illness in smokers
-How smoking can reduce the appetite
Maybe even how it can produce an antipsychotic effect in those with psychotic components of mental illness.
This explains...
-Studies finding greater anxiety and depression in smokers (probably increased suicide/suicidality too)
-Some physical detriments and chances of illness in smokers
-How smoking can reduce the appetite
Maybe even how it can produce an antipsychotic effect in those with psychotic components of mental illness.
Limpet_Chicken
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Hm,schizophrenics are reported often if not usually to be heavy smokers, its not impossible that it is due to dopaminergic effects of lighting up, considering its common for schizos to be on antidopaminergics with nasty as hell side effects, no?
Funny APAP is mentioned, it'd be easy enough to form the active metabolite by formation of the acid chloride of arachidonic acid, protection of the phenol, coupling of the acid chloride with APAP then deprotection of the phenolic function.(anyone know if the short-chain esters of the phenolic function of AM-404 have been explored to enhance lipophilicity? although its probably already high with that great big fatty acid amide group?
AM-404 as a FAAH inhibitor IMO would be fairly safe, with respect to avoiding catastrophic fuckups like with that BIL-compound that left a few people as vegetation and killed at least one of the test subjects, given that AM-404 is the active metabolite of paracetamol and as such has been going into people without horrendous side effects already for a long time already. Would be easy to make, protection of the phenolic function of APAP with a base-labile group, formation of the acid chloride of arachidonic acid with the usual methods, SOCl2, PCl3 etc.perhaps PCl5 given starting with phosphorus it's somewhat easier to make than PCl3, although SOCl2 would be my choice given that excess can be disposed of easily by addition of MeOH, and the byproducts are gaseous so the equation is driven to the right, and unlike the phosphorus chlorides there are no solids left behind by SOCl2 to make workuip more of chore, then deprotection of the phenol.
I've contemplated giving the synthesis a go sometime, its not exactly high on my to-do list, But wouldn't mind giving it a try and testing AM-404 for activtity.
Partly because paracetamol itself has no effect at all on me. I've been given it IV in hospital and taken it orally up to the maximum dose without noticeable effect on pain (I've got a trick knee and trochanteric bursitis, both hips, and I'm on morphine/oxy for it so there is no shortage of pain to test it on), and it just doesn't work, I've wondered a fair bit if some people might not be able to form the active metabolite, AM-404, or if they do, do so only at sub-effective levels, similar to how CYP-P450-2D6 deficient folk will find codeine useless at any dose, and would find tramadol pretty unpleasant at best.
Because APAP has been tried by both oral and parenteral routes enough times to know that it doesn't do a damn thing for me.
Also it seems as though much of the cannabinergic activity of AM-404 is due to effects on endocannabinoid reuptake, rather than it's FAAH inhibition.
Funny APAP is mentioned, it'd be easy enough to form the active metabolite by formation of the acid chloride of arachidonic acid, protection of the phenol, coupling of the acid chloride with APAP then deprotection of the phenolic function.(anyone know if the short-chain esters of the phenolic function of AM-404 have been explored to enhance lipophilicity? although its probably already high with that great big fatty acid amide group?
AM-404 as a FAAH inhibitor IMO would be fairly safe, with respect to avoiding catastrophic fuckups like with that BIL-compound that left a few people as vegetation and killed at least one of the test subjects, given that AM-404 is the active metabolite of paracetamol and as such has been going into people without horrendous side effects already for a long time already. Would be easy to make, protection of the phenolic function of APAP with a base-labile group, formation of the acid chloride of arachidonic acid with the usual methods, SOCl2, PCl3 etc.perhaps PCl5 given starting with phosphorus it's somewhat easier to make than PCl3, although SOCl2 would be my choice given that excess can be disposed of easily by addition of MeOH, and the byproducts are gaseous so the equation is driven to the right, and unlike the phosphorus chlorides there are no solids left behind by SOCl2 to make workuip more of chore, then deprotection of the phenol.
I've contemplated giving the synthesis a go sometime, its not exactly high on my to-do list, But wouldn't mind giving it a try and testing AM-404 for activtity.
Partly because paracetamol itself has no effect at all on me. I've been given it IV in hospital and taken it orally up to the maximum dose without noticeable effect on pain (I've got a trick knee and trochanteric bursitis, both hips, and I'm on morphine/oxy for it so there is no shortage of pain to test it on), and it just doesn't work, I've wondered a fair bit if some people might not be able to form the active metabolite, AM-404, or if they do, do so only at sub-effective levels, similar to how CYP-P450-2D6 deficient folk will find codeine useless at any dose, and would find tramadol pretty unpleasant at best.
Because APAP has been tried by both oral and parenteral routes enough times to know that it doesn't do a damn thing for me.
Also it seems as though much of the cannabinergic activity of AM-404 is due to effects on endocannabinoid reuptake, rather than it's FAAH inhibition.
sekio
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I don't think AM-404 is "druglike" enough to be used as directly. Especially orally; the huge fatty acid is probably metabolically labile and certainly also subject to oxidation.
And you'd likely be able to take advantage of the difference in nucleophilicity between the aromatic amine & the aromatic hydroxyl, presumably it would be enough to do a Schotten-Baumann type rxn with 4-aminophenol and arachidonyl chloride, without dallying about with protective groups left and right.
And you'd likely be able to take advantage of the difference in nucleophilicity between the aromatic amine & the aromatic hydroxyl, presumably it would be enough to do a Schotten-Baumann type rxn with 4-aminophenol and arachidonyl chloride, without dallying about with protective groups left and right.
Limpet_Chicken
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Would an amide be degraded that easily other than by FAAH or MAGL (isn't the latter actually the more important metabolic degradation pathway rather than FAAH for endocannabinoids?) Anyone know if AM-404 is water-soluble? on the one hand its got a hydrophilic phenol function (perhaps derivatization as say, the ethyl or propionyl ester?) and a great sodding nonpolar greasy zit on the other end. I'd be curious enough to try it IV, at least if I could find a vein, at least once, to see if there were any effects, since if AM-404 proved active whilst APAP seems COMPLETELY inactive, that would be suggestive of a metabolic deficiency preventing metabolism of APAP to AM-404.
Limpet_Chicken
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Would an amide be degraded that easily other than by FAAH or MAGL (isn't the latter actually the more important metabolic degradation pathway rather than FAAH for endocannabinoids?) Anyone know if AM-404 is water-soluble? on the one hand its got a hydrophilic phenol function (perhaps derivatization as say, the ethyl or propionyl ester?) and a great sodding nonpolar greasy zit on the other end. I'd be curious enough to try it IV, at least if I could find a vein, at least once, to see if there were any effects, since if AM-404 proved active whilst APAP seems COMPLETELY inactive, that would be suggestive of a metabolic deficiency preventing metabolism of APAP to AM-404.
As for Schotten-Baumann reaction, without regards to synthesizing any specific compound, what with the two phase reaction, looking at solvents commonly used, with base being slowly added to the two-phase aqueous-nonpolar solvent mixture, how does it work when a solvent less dense than water is used? I can see it easily enough when the aqueous phase is at the top, where the base would dissolve in the aq. layer, contacting the aqueous phase first, neutralizing the acid, but where the substrate is dissolved in a solvent that floats on water, how does that work out? presumably nonpolars denser than H2O like dichlor are better than E.g ethers? not a synthesis question, just a general wondering how it works when the aqueous layer is at the bottom, leaving the base suspended in the aq. layer.
As for Schotten-Baumann reaction, without regards to synthesizing any specific compound, what with the two phase reaction, looking at solvents commonly used, with base being slowly added to the two-phase aqueous-nonpolar solvent mixture, how does it work when a solvent less dense than water is used? I can see it easily enough when the aqueous phase is at the top, where the base would dissolve in the aq. layer, contacting the aqueous phase first, neutralizing the acid, but where the substrate is dissolved in a solvent that floats on water, how does that work out? presumably nonpolars denser than H2O like dichlor are better than E.g ethers? not a synthesis question, just a general wondering how it works when the aqueous layer is at the bottom, leaving the base suspended in the aq. layer.
@Limpet
- AM404 doesnt dissolve in water, if any
- should be made in inert, dark container with some BHT or BHA or polymerized to crap by both acid and radical. Use precaution as when treating PUFA with anything
- for less dense solvent , add dropwise using syringe tip pointing at the bottom of flask under basic aq
- AM404 doesnt dissolve in water, if any
- should be made in inert, dark container with some BHT or BHA or polymerized to crap by both acid and radical. Use precaution as when treating PUFA with anything
- for less dense solvent , add dropwise using syringe tip pointing at the bottom of flask under basic aq
Limpet_Chicken
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Hm, if its water-insoluble,which isn't surprising, less interest in synthesis, although I might get around to it some time, I AM curious to know if its a metabolic defect that prevents APAP from having any analgesic effect in me. Up the arse as an emulsion is a lot more practical/safe than DIYing an IV formulation.