• Neuroscience & Pharmacology Discussion Welcome Guest
    Posting Rules Bluelight Rules
    Recent Journal Articles Chemistry Mega-Thread
    FREE Chemistry Databases! Self-Education Guide

  • N&PD Moderators: Skorpio

Chlormethiazole analogs?

L

Limpet_Chicken

Bluelighter
Joined
Oct 13, 2005
Messages
6,322
Location
UK
Are there any chlormethiazole analogs that have been tested and found active as GABAergics?

Are the other halides active? would be easy as hell to make. What about pseudohalogens such as CN, or perhaps another isosteric replacement, nitro, or trifluoromethyl perhaps.

And have any ring-substituted analogs been tried out?

Chlormethiazole was some pretty good stuff, most euphoric downer I have ever tried, out of a fair few benzos, veronal, GBL, the 3 Z-drugs, oral ether...you name it, chlormethiazole beat the shite out of the lot of them.

Take too much however, and there is some sodding vicious, perdition-born hadean stench given off in vivo, literally IN vivo, and coming out of, in every possible manner, thanks to some nasty sulfurous metabolite.

Is the corresponding oxazole active? any known tweaks replacing CH3 at the 4-position? or how about saturating the bonds in the thiazole ring.
 
The oxazole analogue is equipotent - according to the patent I've read. It's not a really productive area, but that's about it (different halides don't seem to be mentioned much).

BTW the only good thing about the analogue is the lack of taste/smell..
 
Bugger fluoroethyl just about anything. Not sure about the metabolic fate of the alkyl group, and I sure as hell wouldn't want to find it turning into fluoroacetate in vivo, as far as possible metabolites of drugs go, that one is about the worst there could be, its a potent mitochondrial toxin that buggers up the krebs cycle, slow, painful, very low LD:50 and pretty much irreversible, treatment is purely supportive, and most likely not of much use.
 
I have no actual reason to back it up, but I am going to guess that perhaps, the SAR of these compounds is fairly limited, I.E to barb-sensitive binding site on GABAa.

Any antagonists/inverse agonists? or has it not been much researched. There are no analogs/homologs in clinical use, I don't think. And like the barbs, unlikely any drug company is going to bother tweaking some of the oldschool downers, for much the same reason as we don't see anybody buggering about with say, chloral hydrate or chlorobutanol.
 
They're not messing with those because they've been studied extensively and have serious health issues.

I could easily see a company bringing out an analogue or close-ish relative as an alternative to benzodiazepines or Ambien. More dangerous though, not sure how they'd look at it.
 
Serious health issues aside from being potent CNS depressants, with a steep dose-response curve? or do you not mean the chlormethiazole analogs, and were referring to the rest of all the ancient old fart sleepers?

And no, I am not talking about my mother there=D

The really worrying thing about barb-site ligands for GABAa is that nasty little habit people apparently have of getting fucked up, and then deciding its a fantastic idea to eat the rest of their stash. IIRC keith moon, from The Who snuffed it from an OD, but whilst having necked a damn load of pills (I would want him buried in a lead-lined coffin packed with active charcoal after that COD) only something like 6-7 would have done him in anyway.

But on the other hand, that stuff is effective, no doubt about it, without being benzo tolerant, to compare, save whatever builds up from the odd use of a one, two, or just maybe three consecutive night heavy dose, once in a while, of nitrazepam, take 25mg, but end up changing my mind about sleeping just at that time, or be unable to sleep.

On chlormethiazole however, not a chance, that stuff is almost as good as alpha2 adrenoreceptor agonists at plain and simple knocking me out for the count, including my rather awful experience with barb misuse, veronal wasn't as certain to cause sleep as a couple of heminevrin capsules. Only GABAergic that in my experience was more so, is propofol.

And before you point it out, I did not self-administer propofol, that was when I had my knee operated on, in combination with fentanyl and one of the fluoroether gaseous anaesthetics.

Incidentally, the inhalational anaesthetic, felt like I much like a hybrid, half way between the effects of inhaled EtOEt and N2O.
Isoflurane I think it was, or possibly enflurane.
 
Last edited:
I would be concerned about an exchange Cl→X, with X being Br or I. While clomethiazole itself lacks alkylating properties in vivo are the higher halogen-derivatives most probably much more harmful in this respect.

Limpet_Chicken said:
Bugger fluoroethyl just about anything. Not sure about the metabolic fate of the alkyl group, and I sure as hell wouldn't want to find it turning into fluoroacetate in vivo, as far as possible metabolites of drugs go, that one is about the worst there could be, its a potent mitochondrial toxin that buggers up the krebs cycle, slow, painful, very low LD:50 and pretty much irreversible, treatment is purely supportive, and most likely not of much use.
Click to expand...
Clomethiazole undergoes extensive hepatic metabolism. Known metabolites in humans are:
* 2-chloro-1-(4-methylthiazol-5-yl)ethanol, major (active!) metabolite, "NL-715", produced by CYP2A6 [1]
* 4,5-Dimethylthiazole-N-oxide-S-oxide, [2]
* 4-methyl-5-thiazoleacetic acid, [3]
* 5-(1-hydroxyethyl)-4-methylthiazole, "NL-272", [4]
* 5-(2-hydroxyethyl)-4-methylthiazole, [4]
* 5-acetyl-4-methylthiazole, "NL-511", [4]
* 4-methyl-5-thiazole acetaldehyde, [4]
* 5-(2-hydroxyethyl)-4-thiazole carboxylic acid lactone, [5]
* 5-ethenyl-4-methylthiazole, [5]
* 4,5-dimethyl-thiazole, [5]​
Furthermore is the thiazole ring metabolically cleaved to give aliphatic thiol-derivatives [6], and a thiol-group added to position 2 of the ring [7]. There were some more (minor) metabolites reported, but I can't find the structures right now. See [7] for more details.
The principal responsible enzymes are CYP2A6, CYP3A4, CYP3A5 and CYP2B6.

References:
[1] European Journal of Clinical Pharmacology (2003), 59(2): 117; [2] Xenobiotica (1985), 15(6): 503; [3] Zeitschrift für Rechtsmedizin (1973), 73: 225; [4] Xenobiotica (1975), 5: 687; [5] Arzneimittel-Forschung (1979), 29: 1655; [6] Journal of Chromatography (1982), 230: 335; [7] Xenobiotica (1982), 12: 813.


Edit: I prepared an overview from the (to me) available literature. Question marks indicate unsure connections.
 
Last edited:
bromethiazole is known, and I'm pretty sure it was not more toxic, but about as potent.

Regarding overdose potential: remember that he died because he was also using alcohol, which this stuff potentiates incredibly. Not sure how deadly it is without any ethanol
 
Ahh didn't know that, doesn't surprise me though.

Should have dried him out and sold hm by the ounce to keith ritchards or ozzy ozzbourne=D

Probably does have a steep dose response curve, just like the barbs, and likewises is likely to share that property of the LD50 not proportionally increasing with tolerance to the sedative effects, as they are both barb site ligands, and I would guess, gate the chloride channel in a similar manner.
 
Hammilton vs. Limpet Chicken, 1:0

"Activity of chlormethiazole at human recombinant GABAA and NMDA receptors."
British Journal of Pharmacology 2003, 140(6): 1045-1050
1 Investigation into the modulatory effects of chlormethiazole at human recombinant γ-aminobutyric acid A receptor (GABAA) and N-methyl-D-aspartate (NMDA) receptors was undertaken to gain insight into its mechanism of action and det. if the drug exhibited any subtype-selective activity.
2 Despite a structural similarity to the β-subunit-selective compound loreclezole, chlormethiazole did not show any difference in maximum efficacy and only a slight difference in EC50 in its potentiating action at α1β1γ2 and α1β2γ2 GABAA receptor subtypes with preference for α1β1γ2.
3 Similar to the previously reported subtype-dependent activity of pentobarbital, chlormethiazole elicited a significantly greater degree of maximum potentiation on receptors lacking a γ2 subunit, and also those receptors containing an α4 or α6 subunit. This also demonstrates that chlormethiazole does not act via the benzodiazepine binding site.
4 Unlike pentobarbital and propofol, chlormethiazole elicited only a slight direct GABAA receptor activation at concentration 1 mM. In addition, the drug did not potentiate anesthetic-mediated currents elicited by pentobarbital or propofol, suggesting that chlormethiazole may be acting via an anesthetic binding site.
5 Chlormethiazole produced weak nonselective inhibition of human NMDA NR1a + NR2A and NR1a + NR2B receptors. IC50's were approx. 500 µM that likely exceed the therapeutic dose range for chlormethiazole, indicating that the primary mechanism of the compounds in vivo activity is via GABAA receptors.​
 
Last edited:
It must be more than a decade since I looked into the QSAR for this class of sedative/hypnotic. I seem to remember that the haloethyl side-chain could be be lengthened as long as the halide stayed on the beta carbon.

US Patent 3401172 deals with the oxazole analogue of clomethiazole.

If you actually look for patents (or any database of papers) for sedative/hypnotics there are VAST numbers. Who knows what the profile of them will be? It appears that because of the intrinsic safety of benzodiazepines in overdose, virtually all research moved in that direction.
 
I'd like to resurrect this thread to chime in that clomethiazole is indeed very nice, far better than any benzo. I imagine them being somewhat similar to Quaaludes, based on second-hand reports: all the ataxia and sloppy disinhibition of being really drunk in a pill, with none of the distressing gastrointestinal side effects and no "I feel like I wanna kill myself" morning after. Those in the know take some non-drowsy antihistamine beforehand to counter the hay fever-like respiratory side effects. I have heard that binge use makes one stink due to certain thiol metabolites, but I haven't taken them with enough frequency to experience this.
 
Yes, that can happen. Only ever binged on it once for that reason. I had to scrap the clothing I was wearing, washing it didn't remove the sulfur odor.

One has to take a fair bit for that to happen though.

And careful, chlormethiazole has a VERY steep dose-response curve.
 
You must log in or register to reply here.
Top