To methylate or not to methylate ... This Q can go for many classes but in particular benzodiazepines with without the triazole ring.

[purplehaze147]

Desmethyldiazepam and oxazepam are some of the worst benzos especially compared to the N-methyl cousins - diazepam and temazepam.

You may come to the conclusion that N-methylation is best based off of the above. What's wrong with that is desmethyldiazepam is only a partial agonist of the benzodiazepine receptors (which means oxazepam likely isn't a full agonist either, and its onset is terribly slow). Other desmethyl benzodiazepines are actually more potent or around the same potency as their methylated counterparts.

There's some conflicting things confusing me though. The methyl group removes a polar bond making the molecule more fat soluble and therefore has an easier time getting to the brain. Like nitrazepam is generally considered more recreational than nimetazepam (N-methyl nitrazepam), but in the case of oxazepam it's the exact opposite. Temazepam, the N-methylated version of oxazepam kicks in quick. Removing the N-methyl from temazepam turns it from being the best benzodiazepine for recreational purposes to the absolute worst.

There's a few other things I wanted to discuss, but let me see if anyone has any input first.

 

[Fertile]

If you think about it, alprazolam has NO amides. It has a triazole ring and an imine.

The triazolo ring binds to to receptor with a much higher nM and it's LogP is higher. The secondary amines in nordiazepam and oxazepam result in lower affinity/LogP and the 3-OH of oxazepam lowers LogP further and provides the body with a convenient moiety for metabolism.

ALL of them are full agonists. The N-methyl of diazepam increases affinity and removes one of the metabolic points benzodiazepines are subject to.

I think brotizolam derivatives have the highest affinity of all benzodiazepines (OK, technically they are thienodiazepines) but they bind just the same.

 

[izo]

The benzo with one of the highest affinities is iirc triazolam.

 

[Fertile]

Possibly, but the LogP of triazolam is about 2.4 (depending where you read) while brotizolam is about 3.9 and that's a logarithmic scale (as the name suggests) so brotizolam is much more potent. Actually, I think zolazepam has the highest affinity but it's LogP is low. All I know is it's used to knock out elephants, It's a water-soluble benzo (well, technically not a benzo but of a related class).

 

[izo]

Yea I know of it. Is it the benzo like that is sold along with o-tce?

 

[Fertile]

Yes, that's the stuff. Did any tiletamine homologues turn up as RCs? I would expect the N-methyl homologue to have a better NMDA/DRI balance and thus be nicer, the idea because I've read trip reports on tiletamine.

Of course, I've read a paper on the QSAR of tiletamine and suggested that swapping the cyclohexyl moiety for a 4-thiane ring would get around blanket bans on the arylcyclohexylamine scaffold. The extra sulfur increases NMDA affinity and LogP so again, the N-methyl would be the place to start.

Benocyclidine is purely a DRI so their is at least SOME basis for constructing a wider QSAR.

 

[izo]

Only had tce 0,5G once, sold as 3meo-pcp. It was great. One of my favorites along ketamine.