It would seem that these somewhat archaic downers have been mostly relegated to the dustbin of history. Indeed, pill-popping lore, which has elevated the likes of methaqualone to near mythical status (and for good reason), seems to have largely bypassed these worthy intoxicants. The shit-drug phenobarbital notwithstanding, barbs, especially the rapid-acting variety, send the user into a drunken, ataxic state of oblivion (so I am told). Nothing particularly awe-inspiring or "spiritually enlightening", but getting fucked-up does have its merits.

Structure-activity relationships for barbiturates are fairly straightforward. The general rules are as follows:

1.) Potency is directly proportional to hydrophobicity and the size and bulkiness of the 5,5 substituents, and inversely proportional to duration of action.

2.) Branching in the alkyl substituents increases potency.

3.) Unsaturation in the alkyl substituents increases potency.

4.) In general, asymmetrical substituents increase potency more than symmetrical substituents.

5.) Substituents that are branched at the carbon adjacent to the barbituric acid ring increase potency more than substituents in which the branching occurs elsewhere.

Thus, 5,5-diethylbarbituric acid, ie barbital (http://en.wikipedia.org/wiki/Barbital), is among the weakest and longest-lasting of the common barbiturates, amobarbital (http://en.wikipedia.org/wiki/Amobarbital) is more potent and rapid-acting than barbital, pentobarbital (http://en.wikipedia.org/wiki/Pentobarbital) is more potent than amobarbital, and secobarbital (http://en.wikipedia.org/wiki/Secobarbital) is more potent than pentobarbital.

As for achievable modes of synthesis, the hardest part seems to be attaching the alkyl substituents, which is usually accomplished by alkylation of diethyl malonate with the appropriate alkyl bromides in the presence of sodium alkoxides. This is followed by condensation and cyclization with urea, again in the presence of an alkoxide.

However, it seems a shortcut has presented itself in the way of certain branched-chain amino acids such as leucine and isoleucine. By nitrosation in the presence of HCl, these amino acids can be transformed into alpha-chloro acids, which can be reacted with aqueous cyanide salts and hydrolyzed to arrive at a substituted malonic acid (in the cases of leucine and isoleucine, isobutyl and sec-butyl substitution, respectively) without the need for alkylation (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv8p0119). Of course, a second alkylation, which can be achieved with readily available ethyl or isopropyl bromide, is in order. Most facile is alkylation with the reactive allyl bromide, which proceeds even in aqueous NaOH, and leads to a potent end product.

Combined with the OTC generation of Na alkoxides by azeotropic distillation of NaOH in a solution of alcohol and toluene or xylene, the result is a pretty straightforward synthesis for those skilled in the art.

Yes that is true. It is due I believe to the differences in the way barbs gate the GABAa chloride channel. Benzos increase the potency of GABA, whereas barbs increase its efficacy also. With a benzo overdose, its quite unlikely to kill, as the body can simply reduce the amount of GABA its releasing. With a barb, that cannot happen, given the more direct gating of the ion channel.

Also making barbs doubly dangerous, more so IMO than other barb-like depressant drugs such as the neurosteroids or chlormethiazole, is the fact that they antagonise the AMPA type ionotropic glutamate receptor. Increasing activity of the main CNS inhibitory neurotransmitter while doing the opposite with the main fast excitatory synaptic transmission makes for an excellent surgical anaesthetic, but a very dangerous recreational drug. Very perculiar mode of action at the AMPAr too, seeming to lock the 'clamshell' shaped receptor shut around the bound ligand, in a glutamate-bound state. Which in effect causes an initial desensitization after stimulation by glutamate, then a very very long lasting inhibition of action potentials, different endogenous or exogenous ligands at AMPARs have very different desensitization kinetics, kainate for example desensitizes only slowly, whereas glutamate does so extremely quickly (and different subunit configurations of the AMPA receptor also have different desensitization kinetics of course, the Q/R editing site affects ion permeability also, primarily, if I recall right, controlling permeability to calcium)

In a patch-clamp study using pentabarbital as ligand, even a 300 second washout time after binding of pentabarb was insufficient to return desensitised receptors to normal, I think reaching something in the region of a 70-80% steady state inhibition of glutamate stimulated current. The result is a pretty profound induction of mental dullness and impairment of memory.

And barb withdrawal REALLY sucks. Surprised it didn't kill me. I have more time personally for depressants with a similar mode of channel gating to barbs, but without the anti-glutamatergic properties. Chlormethiazole for instance. Although the physical properties of that make for a bit of a bitch. Unstable as the freebase in air, the base is a liquid, with a really funky smell...sort of like minty ether, with a slight petrochemical tint to it.

 Not pure vileness, like GBL, but a very potent and odd smell. And its a histamine releaser. I always know when it begins to act after taking it because of a pain in the bridge of my nose. Tried shooting it as the acetate salt, and missed the vein, sure as hell let me know about it too. With say, methoxetamine if I miss a shot and can't easily relocate into a vein, then the only way I know is because of the lack of rush and if its not too deep, and it doesn't accidentally go into muscle tissue then a raised subcutaneous depot can be observed. No stinging, just a slight local anaesthesia. With chlormethiazole I had to withdraw the needle, dilute heavily and plug it after snapping the needle off the syringe by work-hardening it to stress the metal because it instantly stung like hell and raised a bee-sting like welt due to the histaminergic properties. I don't think I administered more than a few hundred nanoliters to a few microliters of the solution.

Synthesis is very easy though, cleavage of thiamine with bisulfite and then chlorination of the resulting alcohol with thionyl chloride or some other suitable reagent. Never done it, I get the stuff on a legitimate script but its known to be a very easy reaction, quite likely one step up in difficulty from preparing GHB from the lactone. Oh...and it MELTS syringes like paraldehyde is meant to if its left in them long.

I am not 100%...but I would be inclined to disagree with that statement.

Both barbs and benzos are allosteric potentiators of GABAa receptors. One of the core definitions of an allosteric modulator is that they are dependent upon the docking of a direct agonist or inverse agonist. Neither barbs, benzos, neurosteroids nor valerians actives/loreclezole bind the alpha/beta2 subunit border binding site of the GABAa binding site for GABA. There aren't many ligands at all that are direct agonists, the binding requirements are quite strict, very few are available that are not built on the isoxazole motif made famous (at least famous, relatively speaking, of people who would know the difference between an ionotropic receptor and their rectal sphincter. If I had the money for a patch-clamp setup I would test that with some phenobarb, , but I won't have that for probably a long time...not sure how much a secondhand axopatch recorder and an amplifier runs to but I bet its much more than I can afford...when I do have more money though, that is one thing I intend to invest in...at least, as long as I can find a way to run tests without cruelty to animals, for I will NOT have a hand in anything like the 'harvesting' of eggs from frogs after inserting a metal probe through one's abdomen to remove eggs for transfection of cloned receptors using gene fragments. I am not willing to conduct research that involves taking anything more than a hair sample, skin epithelial cell swab or maybe, just maybe, spot of animal blood such as could be sufficiently drawn by using a diabetic finger pricker....I could make one run a maze or do other behavioural/psychological test for a reward, but I won't give one ANY drug, certainly not a poison, nor do anything else that could cause an animal subject suffering. I love animals enough that I will capture and remove even the smallest trapped wasp, moth or mosquito unharmed outside)

If patch-clamp assays can be done using cloned cell lines though, then I would have no issue with something like obtaining cells from an animal cancer removed in clinical practise, fused with large cells to create an immortalised hybridoma cell line, as long as they can be, and ARE removed without causing not 'undue' suffering, but any suffering whatsoever and such equipment could be a hell of a lot of use to me.

Any research articles to back up the statement about barbs and efficacy in the absence of GABA? I need none to back up that about benzos, that I already knew for certain.. Personally I stand by what I said about barbs...thats colored I will say, for claritys sake by personal experience. I got into a physical dependency, which after ODing, and getting grassed up to the filth, then falsely arrested by the pigs for alleged 'bomb making'

Jail medical care is utterly shite. Bloody came to in hospital, with two armored filth troops camped outside my ICU ward. Toadface came to visit me in there, and ended up trying, out of his mind with rage, amongst other things, trying to slash a copper\s throat using the sharp edges of a drink can that had been torn open and flattened into an on-the-spot blade. I just wished he hadn't failed. pork everywhere on the street is an affront to my senses and a menace to society.

Got remanded for nearly a year before I was released on bail. Got forced to withdraw from a habit that ran to a bit over an ounce of bio-lab grade barbital free acid in a month, and a legit prescription script for benzos, and opioids on nothing but some shite dose, whatever it was, of chlordiazepoxide (any dose is shite, and that is speaking of a subject without downregulated and desensitised GABAa receptor populations) and a couple of 8mg co-codamols (which would have no detectable effect in terms of analgesia, let alone holding me steady on my pain script even had I never begun to take painkillers for my injury)

I'm somewhat surprised that even though the overdose didn't kill me, the withdrawal didn't. No supervised in-patient detox, which IMO was absofuckinglutely nescessary. Merely handed a few pills with no explanation as to what they were or were for, or explanation of where I was, despite being in full blown DTs and having not eaten for hells only know how long. I didn't even realise food was put in front of me for maybe bordering on a month or so, or what it even WAS for quite some time. Lost so much weight after regaining full consciousness enough to realise, that I resembled a pre-gassed jew. Thinner than an anorexic's dental floss's used dental floss.

Barbs, if you ask me, the cognitive dulling induced by the antiglutamatergic effects lends itself to a rapid drop in both standards and self control, and that makes them both uniquely and specially dangerous. Both in overdose and in general. Toady on the other hand...he was even worse than I. Reports state he was once seen during this time, whilst on barbital, very, very heavily armed, climbing somebody's garden hedge. Not someone he has a grudge against, he wouldn't have a problem exiting somebody who really pissed him off whilst sober but this bugger has done nothing to him GABAergic disinhibition is one thing, but other sedatives, even whilst physically dependent have never done this. The only other one that he could possibly imagine causing messed up shite like this, is zolpidem, and that one is a little different from most, with even a 10mg starting prescription dose being sufficient to render going out for a midnight walk in his underpants an excellent sounding proposition.

Interesting.

As for requiring test animals to assay potential new beta-carboline BZD ligands, this should simply mean the subject is dropped without question, and whatever could come out of it ignored, realising that it can't be done at all. Testing such drugs on animals...thats beyond disgusting, cruelty at its very most abhorrent.

I'm not sure how to translate figures given for concentrations in milli/micro/nanomolar concentrations into what may be presnt in a human body at a given dosage of a compound. Anyone know how to do this?

It suggests barbs do not directly gate GABAa channels at lower doses, only at higher levels. This could perhaps be a reason why low doses are just fine, but when it comes to an overdose the body has no way to compensate and reduce the level of GABAergic activity., and thus carks it. Doubt its anywhere near that simple but with a direct channel gating agonist rather than an allosteric modulator, the potential overdose risks are always more pronounced IMO.

Personally I am more favoured of muscimol. Now there is a direct agonist with some potential.