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benzodiazepines and binding to GABAA subunits ?

K

Kdem

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Mar 14, 2015
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Is it possible for benzodiazepines to bind that GABAA receptors that do not have an alpha 1 subunit ? Such receptors exist, although these are a small minority.
 
GABA-A receptors with a4 and a6 subunits are typically benzo insensitive, alpha 1 subunits tend to lead to high affinity BZ binding while alpha 6 subunits tend to lead to very low affinity.

Studies involving manipulation of GABA-A subunit expression have shown that an alpha1-alpha1 interface is important for Zolpidem's binding, whereas the classical benzo recognition site is the interface of alpha1 and gamma2.

Here is an alpha1 knockout study, it seems difficult to interpret because of compensatory changes but benzos certainly produce effects in alpha1 knockout mice https://www.ncbi.nlm.nih.gov/pubmed/12367614
 
Thanks, the study is a bit old though. Mice born with altered subunit expression may have a different development of their brain, so I don't think that's very reliable for the real world.

Also, BZ 1 and 2 is 'old school'. I'm not even sure what they mean. These days it's alpha 1,2,3,5.
 
Random guess that alprazolam and loprazolam are some of the lowest alpha 1 PAM's of the benzos. Some people state they grant them energy, but that might be due to reducing symptoms of depression? Anyone want to chime in here?
 
Kdem said:
Also, BZ 1 and 2 is 'old school'. I'm not even sure what they mean. These days it's alpha 1,2,3,5.
Click to expand...
Some have classified the different GABA receptors into type I, type II and type III, depending on what subunits they contain/what ligands have affinity for them
 
Showing off here, but wasn't it GABA-A, GABA-B, and GABA-C, whereas GABA-C was somehow a subsidiary of GABA-A? And then things get a bit more specific, even beyond the AM vs OM sites.

This is off-topic, but I was hoping someone with more knowledge (cotcha, sek maybe) could chime in here real quick and explain how barbs act as PAM's at lower doses and POM's at higher doses (or even if that is a valid statement)? Also, of the mechanism of lethal benzo withdrawal (imagine some layman with no knowledge from darknet buys 1000 mg of alprazolam and swallows it at once)?
 
I should clarify what I wrote, the type I II and III GABA receptors refers specifically to different subunit containg GABA-A receptors, but GABA-C/GABA-A-rho is technically considered a GABA-A receptor because it really just contains different subunits (made up of 5 rho subunits)

Barbs tend to be capable of acting as direct agonists at higher doses, making them quite distinct from benzos in that sense (which won't do much in the absence of GABA). Being capable of both opening the channel and stabilizing the channel in its opened state is quite a combo.

Lethal benzo withdrawal likely involves status epilepticus, I would imagine there are autonomic things that can go wrong as well. Or did you mean to type lethal benzo overdose, with regards to the layman taking 1000mg of alprazolam at once?

CY
 
Didn't think barbiturates ever bound to the orthosteric site (at least, of GABAa receptors, IIRC they bind inside the 'clamshell' region of AMPARs), I was under the impression that the reason they were so dangerous in overdose, is that is that benzos increase the efficacy of GABA when bound to BZD-sensitive GABAaRs, which permits the body, in case of overdose, to initiate a compensatory reaction whereby GABA release is decreased. Barbs on the other hand bind at a separate allosteric site but are capable of gating the chloride channel in the absence of GABA, and whilst benzos cause the channel to open more frequently when GABA is bound to a receptor sensitive to BZDs, and increasing the affinity of GABA for BZD-sensitive receptors via induction of a conformational change of the receptor to one in which its affinity for GABA is also increased; but but barbs cause the channel to open for longer, permitting a larger chloride flux per opening event of the chloride channel, can open the channel without GABA being bound, which of course makes it impossible for the body to compensate via decreasing GABA release.

They (barbiturates) are also not as selective as are benzodiazepines, in addition to acting as GABAa positive allosteric modulators, they block both AMPARs and KARs, as well as having some effect on neuronal nicotinic acetylcholine receptors and glycine receptors. Not sure if the effect on strychnine-sensitive GLyRs is as an agonist or antagonist, but as an agonist would make more sense.

As for loprazolam (never taken alprazolam, it isn't available here, and since if I were going to make any benzo then given my very large preference for nitrobenzodiazepines then alprazolam wouldn't be it.), I found it to be quite enjoyable as far as benzos go. Of the benzos that are prescribable in the UK, then nitrazepam and loprazolam are my favourites. Seemed quite hypnotic, and actually euphoric, inasmuch as I've ever found a benzo euphoric (I'm much more a fan of either chlormethiazole or barbs and don't really see benzos as all that abusable, even at 100mg doses or more, even closer to 200mg, I don't find nitrazepam for instance, all THAT euphoric. Pleasant enough but not anything to get worked up about.)


(and speaking of chlormethiazole...mmmm...thats good=D)
 
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Was just musing, probably not to discuss (though don't think there's any documented source of someone fatally od'ing just via benzo)
 
is chlormethiazole even prescribed in the US? i asked few doctors, none of them had any clue :/
 
I think it's considered a drug of last resort, meaning you'd need to find a very ... permissive doctor before you'd get a prescription. Probably up there with trying to get a Rx for Seconal or Desoxyn or the like.
 
Just looking that up now, or trying to at least.

One would think that despite its nature as one of those 'good ol' wallbanger downers' from near enough the dark ages, that most pharmacopoeias would want to retain that one. For use in the likes of inpatient alcohol detox due to its inhibiting alcohol dehydrogenase and prolonging the duration of action of whatever is in the patient at the time, to avoid abruptly landing the poor sods in DTs, while the docs fill them full of anticonvulsants and thiamine.

It also seems to have a quite remarkably low physical dependence potential. At least thats my experience with it (although I'm not taking it for pisspotitis, I use it as seizure prophylaxis and rescue treatment both, have taken it at a minimum of 3x192mg/d daily, some days much more if its been one of those days where the shit is determined to hit the fan), although it doesn't have a license for antiseizure use in the UK at all, only as either an alcohol detox drug or on a short term basis for severe insomnia. For some reason the docs just asked me what I wanted to use to deal with the little fuckers [the seizures that is] and then went with my answer. A lot easier too than getting benzos, IMO just because it isn't one and doesn't end in '-epam' or '-azolam' the docs aren't nearly as prejudiced about using it, even if it is very uncommon, its a lot easier to get than benzos or even those shitty Z-drugs, which I daresay I do find pretty hilarious, not that I'm going to break it down for them about the character of the drug. Then again, I don't have to worry about benzos now either because at some point some doctor was stupid enough to put nitrazepam at 10mg/d on indefinite repeat, automatically printed, signed and left for me to pick up with my pain meds, stomach meds, pramipexole, adrenolytics (alpha2 agonists in both cases) and chlormethiazole.

They just forgot about it, even after I told them I only needed a short course of a benzo during a really shitty train of events I couldn't do anything about. So now I keep my trap shut, because it'd be awfully, awfully hard to get such a script in the first place even the likes of getting a single tablet of a benzo is like pulling teeth. Your own teeth. Out through your ureters. With two pieces of rusty barbed wire. And I just use them if ever I run low on pain meds to keep myself ticking over for a day or two, out cold, on way more of the nitraz than the docs would approve of.

And most doctors here in the UK, where chlormethiazole is most certainly used, a lot of them don't have a clue about the stuff. Which seems to work in my favour. If they did know more about it I doubt I'd have been rx'd it on the same permanent, auto-refilled script as my pain meds etc. are on. Some doctors here can be really clueless at times.

But it is listed as a drug of last resort, for when all else has failed, in the UK and IIRC it also has some kind of neuroprotective effect in alcohol WD, although I can't say as I know what its meant to be or if it extends to the likes of seizures. I like it mainly for the vanishingly little tolerance and zero physical dependency I've got to the stuff even after years of multiple daily dosing. I don't know anything else GABAergic that I could have gotten away with that from, bar really mild things like chamomile tea, lemon balm tea etc.

Definitely quite unique stuff.
 
Isnt clomethiazole toxic to the liver? I have seen old studies of case reports of liver toxicity.
 
Can you link any of them? I'd be interested in reading them. I can't say as I like the look of the structure of the stuff all that much, a terminal alkyl halide isn't exactly the nicest of things to have in the structure of a drug.

Still, however, it has generally speaking had a very positive impact on my life, especially considering how fast the stuff acts, and that if I either know a seizure is about to begin, or its just beginning and I still have a short time to react, or else someone else can dose me with it after I no longer can, it almost always pulls me out of it within a couple of minutes of the capsules breaking open, and it is pretty reliable, and of course there is that absence of tolerance factor that I mentioned, and I really don't know of any other drug that I am sure I could use that wouldn't potentially lead to a rebound type effect. Certainly not GABAergics thats for sure.
 
Clomethiazole is of great utility in cessation of alcohol use in the dependent but is itself dependence-forming. I've seen someone IV them and he explained that you have to be fast... it melts plastic. The oxazole homologue is known. It is equipotent and has the advantage of physical properties that mean it is less damaging when IVed, not that I see that as a worthwhile market and neither did the original developer thus the work didn't go anywhere. Barbiturates are a whole different thing in my experience. Once again, IV use is for those with the self-destruct button taped down. My only experience of them was a few 50mg Tuinals and it ended up with me and a friend waiting outside a bar just so we could start a fight. Anyone who knows me knows that is not like me and we obviously scared people when groups of 6 or 8 still wouldn't get involved.

As for benzos, well I'm able to say that the QSAR is pretty well explored and in the 1,4-pyridinydiazepine class (if that is how you would describe bromazepam, pyrazolam, pynazolam, pyeyzolam and so forth), you can produce α-selectivity (for diazepam-sensitive sites). Pity we didn't get to go through the 1,5-pyridinydiazepine class and possibly the benzoxazinamine class to get a truly full set of QSAR data for the β-1,2 & 3 selectivity as well.

I think it is important to know that it is possible to commit suicide with benzodiazepines alone. One of the drivers for the research was to resolve the issue. Data came from Swedish research and the nitro-bearing derivatives appear to be the only ones capable of killing alone so we explored why that should be the case (metabolite) and how to resolve the issue (modification to prevent metabolism).

I think the most important result we discovered was that alcohol dependence is mediated via the α5β1 subunit. Anyone who is not a dependent alcohol user will become drunk if given pyeyzolam (the 8-ethynyl homologue of pyrazolam) and anyone who is a dependent alcohol user will not develop abstinence syndrome if given pyeyzolam. It was tested on a group of people dependent on 40 units of alcohol per day over a period of 4 weeks. Although a small trial, nobody dropped out and no negative side-effects were reported. One of the most upsetting things I have ever had to deal with is knowing that we could improve and extend the lives of dependent users but not to have the license or indeed the budget to continue treatment. It is such a rare thing to see ones own work help others and so upsetting to know that you do not have the authority to help many more.
 
I wouldn't dream of IV'ing chlormethiazole or bromethiazole. Fuck no. Not in a million fucking years. And I have all-glass syringes aplenty, from 10ml capacity to 150ml and others in between, (no, I don't use these for IV'ing drugs with iffy physical properties with respect to either plastics or veins. I use them when handling chemicals that are extremely aggressive to everything more or less bar teflon in the case of organics, and that don't attack glass. Last time I needed one, for example, was for transferring a batch of iodine monochloride that I synthesized to a glass screw-cap chemical resistant bottle, with the cap being some kind of fluoropolymer, not sure what its made of actually since I didn't buy the bottles, they were left here after a pig raid, they came here demanding to 'take samples', when in actual fact they deliberately damaged parts of my lab, damaged glassware including some expensive ultramicroscale equipment (such as a 5ml pear-shaped reaction flask with an integrated vigreaux and side-arm with a short fluid-cooled condenser with the vacuum takeoff), and they did indeed 'take samples' in that they brought these chemical attack resistant bottles with them, and put a ml or two of various chemicals in bottles, left them on the lab bench and fucked off. So in reality it was no legal raid, but just to come and do damage out of malice. They didn't even take their socalled samples with them, just left them there on my lab bench. I've still got them. And whatever the plastic the cap and the flexible seal underneath is made of is highly resistant to attack, by halogenating agents, halogens, interhalogens, although of course I've never exposed them to any of the halogen tri- or pentafluorides given how outright nasty they are and the fact that if ever I use fluorine gas for anything it'll be for something that cannot be accomplished any other way, not for projects that are just out of interest, or for fluorinations which can be accomplished by other means. The likes of chlorine trifluoride, chlorine pentafluoride are just too damn dangerous for me to want them around. I've heard of chlorine trifluoride burning through multiple feet of concrete then over a meter of packed stone gravel before finally becoming exhausted and stopping. So obviously, not something one can just casually handle, and if at all used, would need investment in designing and building a dedicated safe handling facility before even attempting synthesis or use. PERHAPS I'd go so far as to prepare some of the higher iodine fluorides, but only those of iodine, the iodinated interhalogens being the tamest of them all, although ICl is still a fucking vicious little bastard, I've seen just the tiny traces of vapor that escape from a mated ground-glass joint with the male fitting wrapped with teflon tape thoroughly, utterly destroy a plastic keck clip within ten to fifteen minutes, not being distilled or at higher than atmospheric pressure and in ambient outdoor (UK) temperatures in the colder seasons, it began to turn from the green of a 24/40 clip to being covered with a thick white bloom, then developed splits very quickly, before crumbling away to dust with a few chunks in it, presumably those being derived from the arch-shaped parts that protrude from the back of the clip, being furthest away from the vapor traces, which were low enough to make the ICl in the still pot flask undetectable from outside the closed system.

Just those tiny, tiny traces are so aggressive that within a day or less, they disintegrated a stainless steel keck clip also, causing it to rust away to flakey material that held the shape of the original clip but that when touched with any force, broke down into a pile of oxides.

But these bottles, they withstand interhalogens, chromyl chloride, halogens (E.g Br2), strong acids (I.e 99% H2SO4), indifferent to white phosphorus, strong bases such as alkoxides [never tested them against the likes of alkyl/aryllithiums since they are open-topped and such would need a septum rather than simply be open at the top), but all the very nastiest, most aggressive, oxidizing, reducing, acidic, basic, oxidizing acids, don't touch the cap or seal material) I'd be somewhat surprised if even concentrated hydrofluoric acid did anything to the caps, although of course I'd expect the bottles themselves to be destroyed, but if only the cap and seal were thrown in to fuming HF or even anhydrous liquefied HF then I'd not expect them to be damaged in the process)

So they come in handy for storing larger quantities of chlormethiazole or bromethiazole base, that can then be measured out for oral or rectal dosing with an eyedropper or glass syringe respectively. I've yet to see anything at all, even iodine trichloride kept in a chlorine atmosphere doesn't do anything to them.

As for tolerance, in my experience, chlormethiazole actually seems to produce REMARKABLY little tolerance when used in a medical setting, I take 192mg 3 times daily and have done for years now. And also as needed additional 12 to 21x caps in any given week as a seizure rescue pack kit and, despite benzodiazepine use as well (I keep the benzo use to a couple of doses per week, typically 75-100mg per dose, excluding perhaps, on certain individual weeks, another 1 or two, at most 3 doses of 5 or 10mg 2x/d, but only rarely, either if the shit hits the fan and its instant overloading in whatever the situation is, and its just one of those days one can't get by in one piece without nerves frayed to tatters and generally feeling like total shit through life circumstance, or else if its one of those days where terminating breakthrough seizures is close to closing the door after the horse has bolted, chlormethiazole stopping them before they get off the ground, but can't sleep or else it wears off and another seizure will take place. Then I'll use a few nitrazepam pills for their far far longer action, and 1 or 2 additional chlormethiazole caps.

But, even so, whilst making sure my benzo use is low enough or at least infrequent enough to ensure no dependence formation, the chlormethiazole use, I can if I must, quite literally cease to take it 'cold turkey', but cold turkey only in the sense of abrupt cessation, without any connotation of withdrawal, because at least in my experience there is none.

I don't dispute its capable of causing physical dependence, afterall its a barbiturate site agonist at GABAaRs but much higher doses than I take would be needed. I am absolutely certain, that if I were to take 3x5mg nitrazepam instead of the chlormethiazole, or even 3x10mg diazepam (if it didn't disagree with me and cause paradoxical effects after a long delay, which benzos that metabolize to oxazepam seem often to do) or 3x1mg lorazepam would DEFINITELY land me in deep, deep shit if I did so.

Chlormethiazole is relatively short acting although highly lipophilic, I can't see it being much stored in my body fat reserves because I hardly have any. I've always had the kind of build that is built like a length of thick steel braided cable. Muscle and bone and skin tissues, but body-fat, I'd be surprised if there was very much of any but the brown adipose tissue involved in thermoregulation etc. in me at all, aside from subcutaneous fat, that much I know I have, since after severe wounds, such as a sword cut to the arm, I could actually SEE it there.

So I've almost no fat reserves for xenobiotics to hide in. I'm thin, and built like a whip-cord. But even going without for days, it produces no physical withdrawal in me. Its quite an odd drug in that respect. One would expect a barbiturate-site GABAa agonist to be highly dependence-prone. Perhaps chlormethiazole specifically, induces very little internalization of the receptors, is it known whether the drug produces much desensitization? benzos affect specifically GABA-bound benzo-sensitive GABAaRs, and the body can compensate by reducing the level of GABA, thereby helping to ameliorate the level of depressant activity, whereas barbs, and chlormethiazole can gate the chloride channel directly, bypassing this, so perhaps there being no reduction in GABA synthesis possible as a compensatory mechanism means that the body doesn't do this in cases of the Cl- channel being directly opened, either by a barb site agonist or an orthosteric (GABA binding site) agonist, such as GABA itself, or things like muscimol, thiomuscimol, etc.

I'd be curious to synthesize selenomuscimol some day, obviously the tellurium analog is out completely, since there is no way in all perdition that I am ever willingly going to ingest anything containing Te. It might be one of the most beautiful elements of them all, especially when it occurs as outgrowths of faceted, perfect crystals of 'metallic' tellurium, but its not an element I'd even want to touch with my fingers, let alone swallow a compound containing the element in its structure. For the obvious reason that I don't want to turn into a nuclear-grade walking stinkbomb. I did have that experience once, with a sulfur compound, that caused me to emit some heinous-smelling, potent and FAR-carrying stench for some time. People hundreds of yards off in the open air down the street literally turned and ran. And since the stuff was a metabolite, it kept being produced, and no amount of showering, even for hours on end with several bottles of shower gel, several times a day would stop it coming out of my skin, saliva, nasal fluid, sweat, piss, shit even tear fluid could contaminate a piece of paper so badly that the smell never left it until burnt.

I had to wear the same set of clothes the entire time, until my body had fully done getting rid of it. And going from the difference between say, hydrogen sulfide (nasty, but bearable in subtoxic concentrations) to hydrogen selenide (just...vile..absolutely stomach-turningly, shocklingly vile) and the likes of selenomercaptans, alkyl or aryl selenides/diselenides are beyond description near enough. Real 'fuck ME! run like hell, because hell just turned up on your doorstep', I can only imagine what Te equivalents must be like, and given the notorious tellurium breath from even minute exposure, I've no enthusiasm for seeing what hydrogen telluride, mono/dialkyl mono/di/tritellurides must be like, or something like telluroacetone. I'm pretty sure if ever I were to make seleno or telluroacetone that the chemical warfare response teams would be called in if ever the source of the abomination that gassed my city were discovered. The chalcogens start benign in case of oxygen, although some alcohols do smell foul to me, like isopropanol, but thats just me and personal dislike. Then they start getting nasty when it gets to sulfur, worse by far when it comes to selenium equivalents, and from everything I read, in the case of Te they just become utterly insufferable.

But I would be curious to try selenomuscimol, given that a dose of ordinary, bog-standard muscimol is about 10-15mg, thiomuscimol is more potent than muscimol, and if there is a trend of potency increasing the heavier the chalcogen, then selenomuscimol ought to be highly potent, more than enough to avoid selenium toxicity, assuming the Se content ever becomes bioavailable. And given muscimol itself is excreted more or less unchanged in one's theresa may...ahem...piss, sorry, easy mistake to make there=D, then Se absorption would at most be minimal. And besides, 2C-Se didn't appear to be causing Se poisoning.

Clubcard, have you ever actually TRIED chlormethiazole? and I'm not talking outright stupidity by injecting the stuff...because fuck me, that is way beyond idiocy. Injecting something that MELTS and dissolves plastics aggressively, in plastic syringes (I very much doubt that guy was using all-glass syringes somehow. I might have many of them at my disposal, but thats me, pharmacies aren't going to carry them, and they aren't what one would call common medical instruments these days. And as said, I have never, ever used one to administer an injection, at least, not to me, if a needle is attached to one of mine, it is to add something to a reaction through a septum that would probably cause plastic either to disintegrate on contact, or else burst into flame, or itself burst into flames on contact with air or atmospheric water vapor. Not for shooting up, but for chemistry. And besides, I'd hardly consider IV'ing or IM'ing 150ml of anything a good idea, with the sole exception of blood or plasma expanders in cases of hypovolaemic shock from blood loss. And IM'ing that much liquid would be damaging almost certainly, and extremely painful at the very best. 5ml IM shots aren't what one could call comfortable (5ml rigs aren't avoidable when I'm using morphine IM, because of the 60mg/ml solubility limit, even warming the water until just about comfortable still, doesn't dissolve enough morphine sulfate to give anything even approaching a proper dose.That needs hot water (bearable to the body without discomfort) and a 5ml rig.

I find it much more practical to use it as dipropionylmorphine making use of the acid chloride or the anhydride + a little NaOAc. Been wanting to try 4-DMAP with a little pyridine for its ultra-efficient and rapid, room temperature conversion from the anhydride or acyl chloride and morphine, superhigh conversion to the desired diester, room temp, ten minutes. Nice as it avoids exposing the sensitive morphine or even more sensitive esters to heat. With just a little NaOAc or sodium propionate to promote the reaction all the better. Rather than using a combination of morphine, propionic anhydride or propionyl chloride+NaOAc, and TETA, 4-DMAP/pyridine would allow for the acylation to take off at rocket speed, and be done so quickly that if they were two spacecraft, acylation agent+regular base would be equivalent to sending a shuttle into near earth orbit, or a trip to the moon and back, whilst 4-DMAP+pyridine/acylation agent would have us at proxima centauri within the time it takes to smoke a cigarette and to fart in donald trump's face, if you can call the covering of his skull that and not be sued by faces everywhere.
 
I would be concerned with replacing the -Cl for a -Br in clomethiazole. I would immediately be concerned about it alkylating the body as bromoethane does. I have witnessed someone being given paraldehyde in an RSU (Regional Secure Unit) in glass works and the tissue damage was just awful. Yes, I trued clomethiazole in the early 1980s. As the overuse of benzodiazepines in care homes became a national scandal, a few switched to clomethiazole since it isn't covered by the MoDA (Misuse of Drugs Act) hence no record keeping (at the time). My then partner worked in a nursing home and acquired a few. As for it's ability to cause physical dependence & psychological addiction, well we are all different but there is evidence leading back to the 1960s in the BMJ (British Medical Journal) and a great deal of it shows it produces a particularly abstinence syndrome. I was under the impression that sedative-hypnotics mediated by the GABA receptors reliably produce physical dependence. I'm not saying I'm right, I'm just saying what I was taught.

I have something of an unreasonable dislike of morpine and it's esters because phenolic opioids don't work for me. I do recall a paper I submitted to Lifeline Publcations in 1997 (I think) about the import of ethane-1,1-diyl diacetate (ethylidene diacetate/CAS 542-10-9) into Afghanistan and Iran. It remains an uncontrolled compound, likely because any 1,1-diyl acetate is equally effective as an acylating agent. As you can see, it's just the trimer in which acetic anhydride is the dimer. A solid (convenient to transport), wide industrial usage (plastics) and allowing for the possible mixed diyls, a few dozen (obvious) and (realistically) the possibility of hundreds, it more or less defeats any attempt to use AA & derivatives as a pinch-point. If you read the UN reports, it took a while for it's utility to be recognized but goes a long way to explaining why 2017 yielded a record harvest. I AM happy to see it's use in cases of myocardial infarction but the 2013 shortage (in which morphine was substituted) showed a reduced death rate... so I do question it's more widespread use. I don't believe there should be an ethical problem in providing it to people who are dealing with dependence, I am only moved by the ridiculous pricing.
 
Yeah thats what surprises me. I would have expected chlormethiazole to be an extremely dependence-prone drug. But it just hasn't behaved that way to me. Not saying it won't to others or cannot, but it IS unusual stuff, very much so, to me. I was actively expecting, and regularly testing for dependence by waiting on my first daily dose etc. unless I HAD to, and the only difference was that I had more seizures, the kind I already have and not accompanied by other side effects of any kind, like anxiety (except actually during a seizure should one break through in such a test, but thats because they scare the shit out of me at the time whether I'm on chlormethiazole or not, so I put it down to simply the protection against them being removed leading to more seizures, ones that would have happened anyway but didn't at other times because they cane looking for grief to cause and found themselves getting the shit kicked out of them by the hulking, strangely grey and egg-shaped bouncers with the brass knuckles at the LC cerebral nightclub. Bouncers aren't there? the little shits can get in. But no more little shits than otherwise.

And particularly what, clubcard?

As for bromethiazole, that was just an experiment. Not something I take on a regular basis. I can get a fair bet of chlormethiazole from my doc on rx,and if I wanted more, cleave vitamin B1, separate out the toxopyrimidine (the pyrimidinic fragment is known as toxopyrimidine, and is a potent convulsant due to its vitamin B6 antagonistic effect) and once I'm satisfied it is all gone, then chlorinate the alcohol to produce chlormethiazole, take up in a low-boiling solvent of the chlorocarbon variety which smells like chloroform but without the sweetness and is a lot lower boiling, sharper and whiter, less ripply smelling. (sorry that bit won't translate well, I'm kinda synaesthetic, specifically for some reason in relation to chemistry most of all, thats auties for you :p weird bugger that I am I'd miss my extra-sensory perceptive modes if they were taken away from me, I really would. If DMSO were no longer straw colored and if triphenylphosphine didn't move by looping, like a little fat grey caterpillar, or hexamethylphosphoramide wasn't orangy yellow with grey bits on one end and if chloroform wasn't always felt as being stirred by a silver teaspoon, whilst carbon tet was no longer as flat as a pane of glass,and deep green unlike the white DCM or the ripply lake that is CHCl3)

Anyhow, that procedure (I kept it vague enough that those who don't need to ask will know, whilst avoiding synth discussion)
and then vac distillation (you do NOT want to distill bromethiazole or chlormethiazole at 1atm, they tend to undergo some sort of thermal cracking and/or rearrangement into something that smellsabsolutely unspeakably foul, that even traces from a sep funnel, that had been thoroughly washed and rinsed with boiling water made the lab unusable for days, just because that funnel had been put with that portion of the glassware that will fit in my lab (there is way too much of it to fit in the lab, I pick and choose what I need as I need it, whilst keeping certain items always to hand, such as RBFs of various sizes, test tubes, hotplate-stirrer etc.) and the rest of it has to live in the lounge, the kitchen, bedroom and elsewhere, all packed in crates, at least as much as can fit in the crates I have, such as the one my 5l, 4-necked RBF came in, or that my rotovap came in.) some has to live on a section of the carpet, some under chairs etc. Some on the kitchen cupboards and others on various floors, shelves and tops of shelves. Damn thing is getting bigger than the house. And THAT isn't counting the longterm slow hydrolysis and continual production of ICl experiment to form a concentrated solution of that weird hydrohalic acid that has the formula HX1Y2 where X and Y are chlorine and iodine, although I'd have to look it up again as to which way round it goes. But it does form a perculiar hydrohalic acid, a non-oxyacid which is reportedly a very strong mineral acid.

(been leaving the remains of an ICl synthesis outside, and relying on water vapor slowly coming into the apparatus and hydrolysing it over months, avoiding both violent hydrolysis as would occur if I simply poured ICl into H2O and having to continually watch it. And whats now there is a golden liquid, that is liquid even during snowy weather, have yet to take samples and start testing it by forming salts, fusing them and subjecting them to electrolysis, using the chromyl chloride test to test for quantity of Cl2 per gram of the liquid, test PH, test for oxidizing properties etc. Very unusual stuff, quite unlike my ICl, which is dark in color and freezes semireadily.)


Interesting about ethylidene diacetate. Have you any figures comparing this reagent with the gold standard, acetic anhydride/propionic anhydride (+ scavenger base of course) or with the corresponding acid chlorides? that'd be an interesting thing to look into, yield wise. Likewise, with propylidene dipropionate. Am I to assume the stoich is 2 active acylating units to one less active one, rather than 1:1 with either acid chloride or acid anhydride?

As for morphine you and I have opposing viewpoints then I see. I vastly prefer it to oxy, which makes me feel slightly uneasy. I just wish morphia had a respectable oral BA. Or at least that my doctors in transferring me from oxy to morphine at my request ignored my protestations of not taking equivalency in potency into account, and leaving me with a dose that is already short and which they are badgering me to cut down on! and that I CAN'T take orally, not without withdrawing or only getting a few doses out of a script.


Psychological dependency with chlormethiazole, sure I can see that happening to people who are prone to it with that class of drugs. BUT, and I would really, really LOVE an answer to this question. How is it that I am able to take a barbiturate binding site GABAaR agonist of intermediate duration several times daily, every day, thrice daily, and for years, without coming out with a physical dependency? And more, when I need my rescue pack refilling. Sometimes it can be up to 7-8 caps daily on and off. Yet remain clearheaded, at least as clearheaded as I was to begin with, without physical withdrawal symptoms, and yet have certainly suffered WDs from benzodiazepines, even at 1-2mg lorazepam daily for a short time when I needed it, and asked to end the script as I no longer needed it. I take benzos these days only on a PRN basis, for a few days at a time, albeit at hefty doses, such as 100mg nitrazepam (I've always been hard to knock down with benzos) twice daily over 2-3 days if really needed after a traumatic event (I've an unending script, due to a negligent oversight of my doctors, for nitrazepam, that automatically gets filled and dispensed with the only thing I have to do being to walk in and pick it up on the days that its written up then take it to a pharmacy. THEY think I am using it twice daily, rather than simply keeping them stockpiled for when I really need a benzo, because I KNOW that if I cancelled the script of my own accord, that the resource would be difficult or impossible to get when I actually genuinely cannot go through a day without a benzo, because of some awful event in life, you know the kind of thing, those days which just actively get up in the morning thinking 'hey, fellow circumstances, lets all go dogpile LC or whoever else and make them feel like total fucking lukewarm dysentery squirtings on a burger bun. So that nitrazepam well is going to have its drilling rig kept over it until something makes it impossible to tap so much as a single tablet more, until its drier than theresa may's crusty old cervix after a red hot sand douche (probably one of her relatives, apart from the hot bit, just the bone-dry old douche part)

So anyhow, CAN anyone explain HOW on earth I can take a GABAergic like this, especially one like chlor/bromethiazole and not get a physical dependence, even with the additional rescue packs and occasionally for one reason or another I'll leave unspoken, need a lot of vitamin B1 and some winemaking supplies and SOCl2. Total coincidence I'm sure=D

But how...how the hell? its been years! it just doesn't seem inclined to produce withdrawals in me. Which is one reason, that despite that alkyl chloride, aside from its ultrafast action in terminating seizures, that I love the stuff as my antiseizure med. It has everything I could want-effective, ultra-fast acting, a pleasant tingling in the back of the nose and throat, a nice warming feeling from contact with mucous membranes as the caps break. Pleasant smell. And as far as I can tell, with my personal usage patterns and physical makeup, nonaddictive.

Have you ever handled the ethylidene diacetate? whats it like to handle? how violent is hydrolysis? and do you have any published data I might read about it? I'd LOVE an alternative to propionyl chloride or its anhydride, they are volatile and god is that stench ever heinous. The goaty sweaty bitter tang it leaves in the back of the throat after all is done and its time to remove the gas mask, one breath of air with a trace of the halide or anhydride in it and its enough to make me gag, not because there is a lot of it there, there isn't, its just the sheer foulness of the stuff.

And paraldehyde? do they still use that? jesus. And injecting it? jesus H god, that must have caused tissue necrosis surely? I wouldn't go near the stuff again orally unless I was paid big money to do so, and allowed the drugs of my choice to take with, before and after it for whatever time I needed whatever I wanted. It reminds me of burning rubber tyres and rotten fruit. Its disgusting. One of the foullest things I've ever had the misfortune of smelling (I DETEST acetaldehyde too, its up there with hypochlorites/chlorine gas, selenomercaptans, arsine, H2Se and pyridine. Just things my stomach cannot handle.

Oh, and isopropanol, another one thats as bad. I know that one is unusual but again its just one of those things I seem to be wired to hate with a passion. That filthy white smell, like the way cracked ceramic tiles look if they could ooze pus. Its awful. MeOH doesn't bother me, EtOH makes my throat catch if I have to drink it unless its at least 70-80% EtOH with just a splash of something like elderflower cordial, diluted and added in to make it palatable in one gulp then washed down. But the smell of isopropyl, even on sterilizing wipes makes my stomach absolutely heave. Yet I don't mind many amines, despite people telling me they smell like rotting fish. I actually like the smell of triethylenetetramine for example. That warm, slightly fuzzy-surfaced orange-yellow smell and the sensation of dripping warm rain falling incredibly slowly is lovely.

I find TETA for example as nice as chloroform, or diethyl ether. And I love the smell of both, although I dislike dichloromethane. SOCl2 doesn't smell too bad either. Although I guess I'm weird being a synesthete like that. Paraldehyde is one of the worst A brutal stinker. Having pure, distilled trimer of hangover made physical injected into someone...thats fucked up.
 
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The book to read is United Nations International Drug Program 'Recommended Methods for Testing Opium, Morphine and Heroin'. The presence of ethylidene diacetate was first reported in 1996 (I think) but since a whole series of diyls will work, it remains somewhat unreported which is more an admission that the control of esterification reagents isn't working than anything else. Alkylating agents don't have to display acute toxicity to be harmful. I can remember us using hexamethylphosphoramide, methyl fluorosulfonate & similar. The dangers were implicitly known but didn't actually result in us looking for alternatives. Now its all explicit and people are free to make their own choices. If you have access, I think a capillary electrophoresis of biological fluids in which Br- ions were the object, that would prove or otherwise the inherent safety of a covalent -Br. That is just what I would do - everyone is free to make their own choices.

The Eunoia disc has the papers and patents on the thiazole & oxazole-classes of sedative/hypnotics. It is interesting to see how the contents of a patent have changed. Now we see the overarching terms that are intended to put researchers off researching huge ranges of compounds which isn't good for medicine (IMO). I've not stepped into a lab in the UK since 1995 and I've probably spent less than 50 hours in the other sites we use globally since then. The lead compounds (interesting) and patent criteria (very, very boring) are about it for me. To me, specific compounds are the things that arrive in the post with CoAs. Instrumentation is also dull... until you see just how shoddy Chinese chemistry is. Insane routes using reagents I wouldn't give house-room to. That is why we insist on PiP specifications... we like to go home and see our kids, not end up taking in a lungful of solvent (yep, we get damp material!) and winding up in A&E.

BTW my reading of the PSa is that clomethiazole is NOT covered because it is a prescription medication. That is just my interpretation but if a compound with almost 90s of utility under it's belt is OK to DIY, I would stick with the known.... again, just 1 POV.
 
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Eunoia?

As for magic methyl..damn. Thats pretty extreme, and downright nasty shit. I've never used it, usually I would choose MeI, although largely because I have easy access to red phosphorus and to iodine (got 2kg of RP in the lab currently, originally from sigma, and of high quality so I don't need to worry about sparing a catalytic quantity to make some MeI) and its safer than Me2SO4 etc.

HMPA isn't what I'd call so extreme, just don't breathe it in, etc. wear protective gear. Magic methyl is MUCH more dangerous.
 
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