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.