Gamma-Mercaptobutyric Acid - Worth exploring?

[SeenSoFar]

CAS#:13095-73-3

So, I've seen this topic bounced around theoretically a couple times several years ago, with some people asking about 'Thio-GHB', but I've never really heard of a solid conclusion, or even heard the actual common name of the compound being discussed, so here we go again. Aside from the obvious possibility of it stinking to high hell, does anyone have any ideas regarding this compound or has anyone heard of it being explored before as a possible psychoactive?

I have looked it up on the sites of a few of the big chemical companies, and I have reviewed some of the available MSDSs. A minority list it as a stench hazard, most don't. I'm not sure if this is because those that do just mark that for all thiols, or if those that don't just don't consider 'bad smell' to be a hazard. Another interesting tidbit from the MSDSs I reviewed is that it seems to be corrosive. How corrosive I'm not sure, one lists it as being 'extremely destructive' to tissue, all the others list it as being an irritant to skin, eyes, mucous membranes, and the upper respiratory tract. The LD₅₀ is quite high, even for IP (1950mg/kg in rats) and IV (1200mg/kg in mice) injection, so that tells me that its probably not THAT corrosive in small quantities. Also, the sodium or potassium salts will most likely not have that same property I would imagine. It does seem to have some depressant effects as well, since the MSDSs do mention unconsiousness as a side-effect of exposure several times.

So, all that being said, does it seem like it might be an interesting avenue of exploration? I would be worried about significant hydrogen sulfide being liberated during metabolism, that is if the dose is similar to GHB and it undergoes the same metabolism to GABA via GABA transaminase, which are both big 'ifs'. Anyway, I'd love to hear some thoughts on this!

 

[sekio]

I think it'd be pretty stinky. Typically low m.w. thiols are.

I wonder if it would cyclise to GBL and H2S.

 

[Pomzazed]

Even when not going to ingestion state, i don't think you can even resist vomitting smelling this thing from 30 cm away - -...

 

[Hammilton]

Imagine the news coverage of this...

Worried that your son or daughter may be abusing TGHB? We'll be right back with five signs that should give you cause for concern after these commercials.

The drug den no officer wants to bust

Warning: That Skunk Smell coming from your child's bedroom may not be the marijuana that went missing from your sock drawer

Krokodil Addicts Discover New Ways To Make Themselves Social Pariahs

Prison Guard Union Fights To Create Special Housing for TGHB Addicts

 

[SeenSoFar]

Imagine the news coverage of this...

Worried that your son or daughter may be abusing TGHB? We'll be right back with five signs that should give you cause for concern after these commercials.

The drug den no officer wants to bust

Warning: That Skunk Smell coming from your child's bedroom may not be the marijuana that went missing from your sock drawer

Krokodil Addicts Discover New Ways To Make Themselves Social Pariahs

Prison Guard Union Fights To Create Special Housing for TGHB Addicts

Oh boy! Ahahahahahahahahahaha! I just lost it on the 'Prison Guard Union' headline! The media would have a field day with this one... Sounds like jenkem all over again! Then again, I can imagine law enforcement would just love this. They wouldn't need K-9 units anymore. Just 'follow your nose' right to the big, bad, drug abuser. Before you know it the idea would catch on there would be reports of the CIA secretly adulterating cocaine with some thioester compound that formed free mercaptans in vivo to give cocaine users that Ode D'Rectum... I better shut up before I give someone ideas...

Seriously though, I am considering acquiring a quantity of this compound and doing some experiments to determine things like corrosivity and whether it produces a similar response to GHB in animals and if so, what side effects it produces (such as unbearable body odour). I know that the simple switch from oxygen to sulfur is often far from simple in terms of changes to the properties and pharmacology of the compound, but I am intrigued by this one.

 

[Pomzazed]

Even when not considering any foul smell,
ingesting THIOL in GRAMS scale seems to me to be toxic.... Sulfhaemoglobineae anyone?

 

[Limpet_Chicken]

I wouldn't go anywhere near this one if you paid me.

The idea of some noxious thiol type metabolite building up in-vivo is not so far fetched. Its happened to me once, courtesy of a chlormethiazole bender. That was an awful experience, it truly was quite traumatic at the time. I can laugh about it now, but then, it was bad enough that not only did I need to wait outside my doc's waiting room when visiting for unrelated purposes, but people crossed the bloody street to avoid walking past. Needed to retain the same lot of clothing until I stopped tasting and smelling that well-known and not so well-loved rotting hellspawn anus scent.

Wondered where in perditions name it was coming from at first, not putting it down to whenever I took a leak. Searched my lab high and low, searched the rest of my house likewise, kept smelling mercaptan intermittently here and there, until it became constant, presumably after metabolizing sufficient chlormethiazole to produce an overwhelming stench.

That was dosing at maybe 1.5g at maximum. I cannot even begin to imagine the unpleasantness potentially unleashed by thio-GHB, even worse for consumers, potential issues with the lactone and H2S. H2S is just nasty all round. Gives me the bloody willies working with the stuff, thanks to its cyanide-like toxicity.

Sounds like a delightful candidate drug to be dosed at multiple gram increments.

 

[atara]

I think it'd be pretty stinky. Typically low m.w. thiols are.

I wonder if it would cyclise to GBL and H2S.

(eep!)

Thiols aren't your friend. The stench isn't just unpleasant: it can cause violent nausea. For this reason the PEL for thiols is usually quite low, less than 1 ppm.

 

[aperson444]

I'm not exactly positive about this, but I think that sulfur would cause a lot of steric bulk on the molecule, and if the oxygen is involved in hydrogen bonding with a residue, sulfur would likely have a decreased ability to do so (or no ability at all). Also I'm not sure to what degree thiols (in large amounts) interfere with/produce disulfide bonds.

 

[SeenSoFar]

You are all absolutely, 100% correct about the danger. My greatest fear is liberation of H₂S in vivo, especially if doses on the same order of magnitude as those of GHB are required.

However, there is a possibility, however slim it may be, that this compound will be much more active than GHB and require doses that are much lower. There is a precedent for this, although the case is far from identical. In the case of choline vis-a-vis thiocholine (a.k.a. cholinethiol), which is choline with a sulfhydryl group substituted for it's hydroxyl, there is a dramatic increase in potency. Choline is virtually unable to produce a depolarization even at concentrations of 40,000 times that required for acetylcholine to do likewise. Thiocholine on the other hand, is able to produce a depolarization at less than 10x the concentration required for acetylcholine to achieve the same result.^[1]

Now, while this is not any sort of evidence that we should expect a similar result in the case of GHB vs. 4-mercaptobutyric acid, the parallel is an interesting one. The idea of a direct precursor to a simple neurotransmitter gaining a huge jump in potency with the simple substitution of a sulfhydryl for a hydroxyl group is very intriguing. I'm wondering if animal testing is in order...

[1] - http://books.google.ca/books?id=apqXDLHzGEoC&pg=PA78&lpg=PA78&dq=cholinethiol&source=bl&ots=bIj6IOXFAh&sig=gNBX3pHsqIuyLdBfpG40KNpsCm4&hl=en&sa=X&ei=J_5tUufGJNil4APV7oGQCQ&ved=0CC4Q6AEwAQ#v=onepage&q=cholinethiol&f=false

 

[Transform]

Irreversible allosteric modulator of GABAa?

There are so many things about this compound that make it frankly frightening.

 

[cannibalsnail]

Sounds fun. A few hours of sedation followed by non-stop siezures which can't be stopped because you blocked up all your GABA receptors.

 

[SeenSoFar]

Irreversible allosteric modulator of GABAa?

There are so many things about this compound that make it frankly frightening.

REALLY?!?! Where did you find that? I must have missed it. That sounds horrifying!!

Sounds fun. A few hours of sedation followed by non-stop siezures which can't be stopped because you blocked up all your GABA receptors.

I don't think that would be the result, if indeed it was an irreversible ALLOSTERIC modulator of GABA_A, since by nature an allosteric modulator doesn't block the main binding site of the receptor. GABA would still be able to bind, so it would not have the effect of blocking your GABA receptors. Benzodiazepines are an example of PAMs at GABA_A, that's why a benzo overdose without any coadministration of other depressants will not kill you, since it is not directly agonising the GABA site on the GABA_A receptor, but rather just changing the way the ion channel responds when GABA binds to that receptor.

Depending on how the receptor responded to an irreversible positive allosteric modulator, I could see three possible results:

1. Sedation for a time, then eventually that site becomes downregulated and becomes unusable until that receptor is replaced. So essentially the ligand acts initially as a PAM, then as a silent antagonist at that site for as long as it takes for that receptor to be regrown, OR

2. Sedation for a while, then that whole receptor becomes downregulated/deactivated and symptoms of GABA insufficency (stimulation, excitation, convulsions, etc) result for as long as it takes for that receptor to be replaced, OR,

3. Sedation results for as long as it takes for the receptor to be replaced.

Either way, its not a pretty picture. 2 and 3 are both horrible in their own ways. Depending on what allosteric site this compound binds to, if the first possibility occured, it would almost be like a self-addiction-limiting substance. You can take it once and get the desired effects, but soon no matter how much you dose you will get no effects, since all the sites are occupied and inactive, you just have to wait for your receptors to be fully replaced. If it bound to a unique allosteric site (unlikely) that would be interesting, otherwise it could be used like a long-term antagonist for whatever site it was active at. Imagine if it bound to the same site as ethanol, I could see it be used as a treatment for alcoholism...

Anyway, all of that is just wild conjecture. I've never actually heard of an irreversible GABA_A PAM before, so I would love any info anyone has on such compounds. I'd also very much like to see where it was discovered to be an irreversible allosteric modulator, Transform. That will make for some interesting reading.

 

[Transform]

Sorry I was just speculating based on sulfur's track record.

 

[SeenSoFar]

Oh ok. What was your reasoning for GABA_A selectivity? I would have guessed GABA_B, based on GHB being selective there, but given its similarity to GABA, I would think either is possible, or it could even be possible it is a non-selective GABA (ant)agonist/(P/N)AM. Or it could be some hideous toxin with no GABA activity at all, who knows. After seeing so many failed guesses about SAR, I'm starting to see why Shulgin takes the attitude he does towards guessing the activity of an unknown compound based on SAR...

 

[Transform]

I just misremembered, it'd probably be GABAb you're right.

 

[atara]

The thing about thiocholine is that acetylcholine, the native ligand, has a much bigger substituent on the C-terminus, and it isn't a hydrogen bond donor. In the case of GHB, GHB is the native ligand, as far as anyone can tell; acetyl-GHB has basically no affinity, and GHB itself is a hydrogen bond donor with a small substituent on the C-terminus. G-thio-B has none of these characteristics, so it'd be extremely unlikely for it to achieve the same potency increase, if it has any activity at all. More potent GHBr ligands include gamma-hydroxy-trans-crotonic acid and 3-chloropropionate, both of which are smaller than GHB itself.

Will a thiol be a likely covalent/destructive receptor ligand? I wouldn't think so; thiols are more reactive at high pH, which isn't found in vivo. GSH is abundant in all bodily tissues without such effects. They can do some strange things, but not this.