Adinazolam and more effective Triazolobenzodiazepine antidepressants

[clubcard]

OK - I was interested to discover that 3-ring nitrobenzodiazepines act as hypnotics because of their a1 affinity and the to now unnoticed effect that they are serotonin releasing agents. Now, the 4-ring (triazolo) benzodiazepines have little to no a1 affinity thus starting with alprazolam. simply swapping the 8-Cl for an 8-nitro produces prompt antidepressant (within 60 minutes) effects. I have tested the nitro analogue of alprazolam ($629/Kg) and the nitro analogue of pyrazolam. I do not know if a '2 -F or '2-Cl increases the serotonin releasing effects BUT as far as I can tell, such compounds have a huge TI and the nitro analogue of pyrazolam (pynazolam) is excreted unchanged.
If people are unaware, nitro benzodiazepines are most commonly used in successful suicide attempts which I posit is because generally the aromatic nitro is reduced to the aromatic amine. This is just a theory but I do think we have a new medicine waiting to be used. The TI of pynazolam is HUGE, I mean >500 (ran out of material and don't like killing animals) in animal models. I think it was Labrat who said 'don't send a rat to do a mans job' but I do not have a death wish.
I do hope someone has the chance to study this more. It would make an excellent pHd thesis, I suggest. If you want notes, boy, do I have notes.

 

[Nagelfar]

Are the 2,3-benzodiazepines also serotonin releasers? It's the 2,3's that are reuptake inhibitors aren't they?

Edit: yes GYKI-52895 is the compound I am thinking of.

 

[clubcard]

GYKI-52895

DRI - so I bet the drug you named mixed with the 8-nitro analogue of pyrazolam (pynazolam) would mimic MDMA.

How about that - benzos that are MDMA-like.

There are a couple of triple-reuptake inhibitors that are JUST like MDMA specifically 6-methyl indole alkyl amines. Requires optical resolution but unwanted enantiomer can simply be racemized so everything get's used. Various 1960s Upjohn patents and papers deal with it.

 

[Nagelfar]

There are a couple of triple-reuptake inhibitors that are JUST like MDMA

So in general would you say a proper reuptake inhibitor, if numbers are right, can be indistinguishable from a releaser? I agree with you there but want to ascertain whether you'd say that's possible generally. i.e. a reuptake inhibitor that is just like meth

 

[clubcard]

I think there is a subjective difference in releaser/reuptake inhibitor/turnover reducer. Most certainly the onset i.e. pynazolam acts very abruptly over 1-2 minutes so I suspect a medicine would require a prodrug.... and their are LOTS of potential prodrugs besides those that reside on Wiki pages.

 

[Flynnal]

If people are unaware, nitro benzodiazepines are most commonly used in successful suicide attempts which I posit is because generally the aromatic nitro is reduced to the aromatic amine.

I can vouch for this. They are almost as dangerous as barbiturates as far as the potential for respiratory depression goes. But they are still generally a bit safer than barbiturates.

 

[Cotcha Yankinov]

I think there is a subjective difference in releaser/reuptake inhibitor/turnover reducer. Most certainly the onset i.e. pynazolam acts very abruptly over 1-2 minutes so I suspect a medicine would require a prodrug

One way to help skirt the delay in onset of SSRI efficacy is to block the autoreceptors (Pindolol), there is a bit in this paper about desire to develop a mixed SRI/5-HT1A autoreceptor antagonist. This is certainly a dangerous idea, but I'm wondering if one could get SRA-like effects from an SSRI with proper autoreceptor blockade. Although its difficult not to block the post-synaptic receptors, and I think the type of release (eg phasic vs. tonic) would probably still be different in SRIs vs. SRAs for starters

A bit off-topic but have you guys checked out Lasmiditan? Fairly selective 5-HT1F agonist that causes some benzo-like effects in some folks apparently, out of 52 targets the only other target it had some affinity for was GABA-A displacing 3H-flunitrazepam (Ki 0.29 mM at 1 mM concentration) but supposedly didn't have any intrinsic efficacy whatsoever (results unpublished). I was wondering if it would be reasonable to draw a conclusion that you could make a mixed GABA-A/5-HT1F ligand, but I leave that stuff to you SAR guys

The following "trip report" from Lasmiditan is I suppose possibly some sort of vascular consequence but thought it was interesting all the same, psychedelic effects from a 5-HT1F agonist (source: some poor migraine sufferer on Reddit)

Spoiler: "trip" report

"About 30 minutes later I tripped out so hard, I don’t even know wtf happened. I started panicking because I couldn’t read, couldn’t form sentences, couldn’t understand what was happening (severe mental confusion), couldn’t walk straight, started seeing trails on everything, having violent tremors, racing heart, couldn’t keep my mouth moving to form words, couldn’t remember basic words, and vomiting. In addition to all this fun stuff, I felt like my arms were gummy arms/legs- I would reach out for my water cup and it appeared like my arm was stretching waaaaay far away to reach it. I also had trouble judging where my water was and had difficulty connecting my hand to the glass. I got to enjoy feeling like I was falling for hours straight- like on a roller coaster I couldn’t get off of. When I went to the bathroom, the room spun around me and I saw patterns on the wall that weren’t there."

 

[clubcard]

I can vouch for this. They are almost as dangerous as barbiturates as far as the potential for respiratory depression goes. But they are still generally a bit safer than barbiturates.

The TI of nitrobenzodiazepines is higher but in cases of intentional overdose, the result is much the same. Sweden has unrivalled data on nitrobenzodiazepines and suicide.

 

[Flynnal]

The TI of nitrobenzodiazepines is higher but in cases of intentional overdose, the result is much the same. Sweden has unrivalled data on nitrobenzodiazepines and suicide.

So they are as lethal as barbiturates in the case of deliberate O/D?

Wow, that's interesting.

I always knew the TI of benzos were much better than barbs.

At least they are safer with accidental O/D which was the main reason why barbs were phased out.

 

[fastandbulbous]

Surprised no one has mentioned the antidepressant effects of etizolam. I think the thienyldiazepines (well the triazolo compounds) would be a very productive direction, for any research to go.

 

[Bare_head]

Interesting f&b says that.

Etizolam was the one substance i struggled to stop and ultimately got an addiciton too.

It was much more euphoric than valium say. What would be the main pharmacological reasons for this?