question about ghb metabolic pathway

[(zonk)]

https://www.ncbi.nlm.nih.gov/pubmed/16673403

^^All metabolic pathway diagrams seem to indicate succinate is end of the line. This article (if i'm reading correct) calls it a PREcursor and has similar action in and of itself?
Unfortunately the semialdehyde is incredibly expensive, hard to find and apparently hard to synth.

 

[sekio]

By succinate, they mean the anion of succinic acid, either HO₂C-CH₂-CH₂-CO₂^- or maybe also the dianion, which are the species you'd find at biological pH. Succinic acid is present in basically every single living thing that uses the citrate cycle ("the sequence of reactions by which most living cells generate energy during the process of aerobic respiration."), is FDA Generally Recognized as Safe (notably GBL, GHB, and BDO are not), and is widely used in flavoring (its esters are also used in fragrance).

As far as I'm aware, the metabolic oxidation of alcohols to aldehydes is reversible, but the oxidation of aldehydes to carboxylic acids is irreversible. Otherwise you'd be able to get drunk by pounding shots of pickling vinegar from conversion of the acetic acid back to ethanol. So back conversion of succinate to GHB seems implausible to me.

This paper states that they found succinate binding to GHB sites when directly applied to cells in a culture dish. However they measure a binding affinity of nearly 200-fold less than that of GHB, which is surely outside of the concentrations of succinate you'd be able to find in a human's brain. (if you assume it's the exact same pharmacokinetics as GHB, then a dose would be in the range of 300 - 500 grams) Unlike GHB, succinate is quite a bit more polar (and also cannot turn into a cyclic lactone) and also more likely to be electrically charged in vivo, so I doubt you'd be able to increase concentrations in the brain by any sort of external administration (IV sodium succinate? no thanks). It's also used as a carbon/energy source by your body so the half life of succinate in cells is probably not very long.

So yeah, in summary, I disagree with their conclusion that "we suggest that succinate (and possibly drugs available as succinate salt derivatives) can mimic some of the actions of GHB." It binds, weakly, to GABA_BR but it just can't cut it as a drug.

 

[(zonk)]

thanks for clearing that up, I knew it wasn't correctly stated lol, like how did anyone miss this?
Slightly on topic, How would succinaldehyde fit into this pathway? What does it mean by highly reactive, is that something to be cautious of too and in what way?

 

[Hodor]

thanks for clearing that up, I knew it wasn't correctly stated lol, like how did anyone miss this?
Slightly on topic, How would succinaldehyde fit into this pathway? What does it mean by highly reactive, is that something to be cautious of too and in what way?

Succinate can be converted to alpha-ketoglutarate via the Krebs cycle, which is then transaminated to glutamic acid, then metabolized into GABA by glutamate decarboxylase. GABA transaminase converts it into succinic semialdehyde, which can be reduced to GHB by succinic semialdehyde reductase.

So succinate is both a metabolite AND a precursor for GHB, although there are only two metabolic steps from GHB to succinate, and 11 steps from succinate to GHB.

As for aldehydes being "highly reactive", I think there's little reason to worry about succinic semialdehyde toxicity; it's just that trying to produce aldehydes is usually fairly tricky (whether you are an organic chemist or a living organism).
Since the step from aldehyde to carboxylic acid is so energetically favorable, trying to make aldehydes (in an aqueous medium) by oxidizing the corresponding alcohol is usually going to result in your aldehyde molecules immediately being oxidized *again* to form the carboxylic acid. Trying to reduce an acid is also kind of a bitch - any reducing agent powerful enough to do this step is likely going to continue reducing your aldehyde to form an alcohol.

Luckily for us humans, our bodies have enzymes, i.e. ultra-efficient, highly selective biocatalysts, but even so the reduction of acids is often done in a roundabout way.

 

[Limpet_Chicken]

Aldehydes themselves, at least in physiologically significant quantities do tend to be somewhat hard on the body, though.

As for reduction of an acid, then to an aldehyde would indeed be difficult, it would be more practical to reduce all the way to the alcohol followed by the use of a selective oxidizing agent which oxidizes alcohols to aldehydes without overoxidation to the carboxylic acid such as chromyl chloride in an Etard reaction (now hows that for a reaction name, if its going to be used for making drugs?), pyridinium chlorochromate or pyridinium dichromate. (note that any concerns you might have concerning the reactivity of aldehydes, or toxicity thereof are so belittled by the likes of chromyl chloride, that they fade into nonexistence comparatively speaking. CrO2Cl2 being a reddish-brown liquid that looks like bromine, has some of Br2's escape-artiste tendencies, is a fuming, damn corrosive compound that hydrolyzes violently on contact with water, fuming off HCl, leaving hexavalent chromium [carcinogenic and generally bad news] and in the presence of atmospheric moisture, fumes off HCl strongly. Oh, and it likes to set things on fire. It really likes to set things on fire. It needs to be used in very unreactive solvents, typically dichloromethane or chloroform, carbon tetrachloride etc, if DCM isn't to be had, because it causes many solvents and other organics to ignite on contact.

I've used it before, made it and distilled it, so it IS something that can be handled in a home lab. BUT it does mean one needs to be able to safely cope with addition of concentrated (98-99% is adequate, doesn't have to be utterly anhydrous, at the expense of some yield to hydrolysis by the trace water content) sulfuric acid to the correct molar proportions of a dichromate salt and NaCl or KCl, then refluxing with a good condenser or stack of condensers protected by a drying tube followed by replacement of the dessicant tube with a stopper lubricated with a perfluorocarbon grease and distilling the product directly at about 120-125 'C (boiling point is 117 'C), again using a dessicant trap on the condenser/s attached to the receiver, perfluorocarbon greases only, unless one is going to use concentrated sulfuric acid to lubricate the ground glass joints)

Volatile hexavalent chromium source that reacts nastily with water and would like nothing better than to sear the flesh from your bones, eat your face off, give you cancer if there's anything left of you, turn your lungs into a slushpuppy and leave acid in it's wake. Lovely, friendly stuff that likes to set things on fire, but doable. And survivable. Although if spilled, you don't want to be on you. I did, once, or rather, a flask failure resulted in about a liter of boiling chromyl chloride (not in solvent, this was during a synthesis) hitting the lab benchtop. Promptly charring the bench-top to ashes soaked in virulent, corrosive, smoking, HCl-belching carcinogenic unpleasantries wherever it hit. Thankfully it didn't slosh over the entire bench, since ground zero became porous enough to help absorb some of the liquid pretty quickly. So I could salvage the structure by sawing out the section which had gotten cooked extra-crispy and disposing of the carbonized shite that used to be bench-top as hazardous chemical waste at the relevant section of the municipal waste dump, after hydrolyzing any remaining chromyl chloride, carefully, with water misted over it while wearing protective gear, to avoid their being exposed to the CrO2Cl2 itself; and effecting a repair by cutting a suitable panel to shape and size and nailing it in. Damn glad that I have quick reactions and was able to get the hell out of the way rather than end up doused from waist to feet in boiling chromyl chloride though and that the worst of it was the waste of the resources put into my synth run for the chromyl chloride and having to do it all over again.

Not intended to scare you off trying. Rather, intended for you to get a good idea of what your up against and what an accident of the critical failure type looks like and what a worst-case scenario would be, if it were to hit flesh rather than a lab bench.

Still got a hole burnt in the floor too as a permanent reminder to be careful as hell around CrO2Cl2 and to always say a quick prayer to the gods of personal protective equipment prior to use. (and to keep my wits about me and stay quick off the starting blocks if a situation mandates getting the bleeding hell out of the way and making an exit in the shortest time possible)

And ugh...I hate losing glassware. Its like losing at least a cherished family pet (I don't have kids...but I confess, I mourn broken glassware more than I ever did my own mother when she died, although if that seems like I'm a bastard, she was suffering at the time, for a long, long time from severe MS and dementia, and had nothing left in her life, so her death was a good thing, and something I'd have caused myself if it were not for the legal ramifications..NOT ending her is something I do feel some sorrow and guilt, for being unable to do it due to the legal risk)

Losing a flask or condenser is way worse than her death was. One gets to have favourites among one's glassware pieces.

 

[sekio]

Chromium (VI) reagents are so old school. If you can get your hands on some you should find some CrO2, the stuff they used to use in magnetic tape, supposedly it's a magnetic oxidising agent that will do alcohol->aldehyde conversion, easy as pie, and you regenerate it in a muffle furnace.

For bench chemistry, TEMPO oxidations are muy preferible. Catalytic amount of TEMPO, KBr, and then add bleach... no chromium shit to clean up afterwards. Working with chromic acid is bad enough, chromyl chloride is right out.