• 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

Euphoria from (particular) benzos...mechanism(s)?

L

LuxEtVeritas

Bluelighter
Joined
Jun 29, 2007
Messages
927
Location
Enlightenment
Anyone know what mechanisms/pathways are eliciting the euphoria that is notable amongst some benzos and more or less absent from others

GABA subtype profiles?
??????
 
benzodiazepine%20backbone.jpg
 
Having a methyl on the 1 position certainly increases euphoria:

Oxazepam<Temazepam
Lorazepam<Lormetazepam
Nitrazepam<Nimetazepam

Other substitutions at the 1 position seem to decrease activity in most cases

Halazepam<diazpeam

Then, replacing the amide with a triazolo ring makes things better.

Diazepam<Alprazolam

A methyl side-chain coming of the triazolam ring makes things better as well...

Estazolam<Alprazolam

Other side chains can increase potency more.

Alprazolam<Adinazolam

A '2 halo group makes the drug a lot stronger

Nimetazpem<flunitrazepam
Cllonazepam<Nitrazepam

Replacing the amide with a thioamide reduces T1/2

Quazepam<halazepam

Some unusual 1 position substitution

Cinolazepam
doxefazepam

Replacing the benzodiazipines benzene ring can reduce the T1/2 while maintaining potency.

Brotizolam
Etizolam

But some reduce potency

Bentazepam

The most potent replacement of the benzene ring seems to be pyrazolo analogs. They also have good water solubility. The toxicity may well be an issue, having said this.

Zolazepam

It's possible to make stimulant benzos.

GYKI-52895

Ones that replicate the effects of alcohol

QH-II-66

And ones that reverse the effects of alcohol and benzodiazipines

RO 15-4513

Or just the effects of benzodiazipines

Brentazinil

The area currently being studied the most is the subtitution of the 1 position but as some of these agents prove, the 7 position can make or break a benzo. Cl,Br,NO2 are agonist, N=N=N are antagonists and CCH (ethylene) produces agonists at certain sites. The '2 can be F,Cl,Br or =N- as agonists. Doesn't seem to confur antagonist properties.

One place that there has been little research is the substitution of the 3 position. -OH, -COO are sometimes used, these reduce the T1/2. Since many benzos are oxidised at the 3 position before being expelled, 'hardening' this site might well improve T1/2. Meclonazepam puts a methyl there, but the methyl can easily be oxidised. If a fluorine were placed there, then the drug should be hardened.

I would be interested to see if anyone has further experimented on the C ring. It has been replaced with a pyridine ring (bromazepam) which retains potency, but reduction to a cyclohexene ring reduces potency (tetrazepam) greatly. A 2 thienyl group would seem to be a logical step although this would surely decrease the T1/2
 
Last edited:
I am more curious as to the biochemical pathways involved as i am familar with the structural features of the more euphoric compounds of the class

such as if it is GABA modulation subtype selectivity profiles or increased action at other NT pathways...et al.
 
What about the cyclopropylmethyl group on Flutoprazepam? It's reported to be awfully recreational by the Japanese.

It's hard to find an actual paper about the receptor subtypes all these different benzos bind to.
 
^Well, it's 1 position is safe, so that's + for the euphoria. Other than that, it's fludiazepam (Erispan) which I know to be euphoric ;)
 
I like the sound of a stimulant benzo. But, to be fair, the compound GYKI-52895 is considered to be a DAT inhibitor with a bit of nicotinic activity, so it doesn't really bind at the benzo allo-recognition site on the GABA-A receptor.

I think that the best benzo (or non-benzo agonist) would be one that is selective for the a2b2y2 and a3b2y2 GABA-A receptors, hence, one might anxiolysis without too much sedation.
 
Particular GABA receptor subtype activation or a combination of certain types concurrently..? Look for patterns of euphoria and subtype selectivity maybe?
 
One point I mentioned in the other benzo thread is that we really can't agree what constituted "euphoria" in a benzo.

It seems many people find Alprazolam euphoric though, but my only explanation for that is that, for these people, "euphoria" means lots of ataxia and amnesia (and sleep?).

Then you have people who equate euphoria with potency. Well, most people would agree that temazepam is more euphoric than alprazolam...

For me, euphoria is clear-headedness with warmth (that is the keyword) and muscle-relaxation (and Etizolam was the benzo for that. Short of that, Diazepam comes the closest).

So what exactly is it that we're trying to talk about here?
 
blissed out sense of ease and well-being...'intense' peacefulness, "happiness'/utter contentedness

euphoria is def not the right term even if one enjoys ataxia, simple "spaciness", et al
 
I've found Ambien to be somewhat "euphoric", though I hesitate to use that word. It and Temazepam were the only GABAergics I found to be enjoyable. I've tried Diazepam, alprazolam, and chlordiazepoxide with nearly no mood boost. Lorazepam was alright, but again, no mood boost.

Temazepam and Ambien shared some sort of stimulatory activity. They both made me want to do things, fiddle with things, work on projects, etc. That reeks of a bit more dopamine-based exploratory behavior. Ambien is perhaps my favorite recreational pill. All other benzodiazepines, my least.
 
Out of all drugs, benzos seem to have the most individual variation between who prefers which one.

Personally I really didn't like temazepam much at all, but nitrazepam was great...and alprazolam is ok and I thought it was much more clear-headed and less sedating than temazepam!

I also find zolpidem (ambien) somewhat euphoric, although not as good as some benzos.
 
i believe if one looks at general consensus there is definitely some benzos that are far more highly seen to have a quality of euphoria and sought after for such reason (though indeed individual variance is somewhat high perhaps here and that may even be an indicator of something :) )
 
Riemann Zeta said:
I think that the best benzo (or non-benzo agonist) would be one that is selective for the a2b2y2 and a3b2y2 GABA-A receptors, hence, one might anxiolysis without too much sedation.
Click to expand...

This is of course assuming that the mechanisms of benzo-induced euphoria overlap with those of anxiolysis and not sedation.

There seems to be so much variation in the recreational effects of benzos between different people that I'm not sure there is one unifying mechanism of benzo-induced euphoria.

I think a lot of it simply has to do with how quickly the benzo can get into the bloodstream, cross the BBB, etc. Alparazolam, triazolam, and flunitrazepam are generally considered to be the among the more abusable benzos, and they are faster acting than most of those considered to be less abuseable.
 
I have some non-sedating, relatively purely anxiolytic benzos at my research disposal and i do not think simply that factor (simply, as that is not simply say one subtype et al) is what will qualify a euphoric tendency as such

maybe some 'high' dosings are needed to approach this
 
Well, benzos bind at the a1,a2,a3 & a5 GABA A subreceptors.

I think a1 is linked to hypnotic and amnesia effects
a2 & a3 are about stress/anxiety

a5 - I don't know.

I suspect the different benzos bind to each of these 4 differently. Nearly all the benzos have a chlorine at the 7 position. Only 5 have a nitro group, those being nitrazepam, nimetazepam, flunitrazepam, loprazolam & clonazepam. Of those 5, the first 4 are hypnotics. I would suggest that the nitro group leans towards the a1 subreceptor.
By the same token, the amide being secondary or tertiary makes a difference to the euphoria. tertiary being more euphoric and longer lasting.
Lastly, putting a halogen on the '2 position increases potency. Fluorine seems to be the most potent and doesn't 'colour' the effects. Diazepam & Fludiazepam feel almost identical.
Oh, and the triazolo ring system is more hypnotic if it doesn't have a methyl attachment. I bet if they put the triazolo group onto flunitrazepam it would be very potent indeed (stronger than triazolam?)
 
well perhaps as first noted it is subtype selectivity wherein there is a specific subtype that yields the characteristic euphoric nature and thus greater selectivity for that enable that aspects to be brought out more prominently and at dosings that are 'palatable'

i suppose if we were able to access a chart for selectivity of the various benzos we could confirm the subtype or negate this theory
 
You must log in or register to reply here.
Top