Indeloxazine

[Poodles!]

I mentioned this in a Tramadol alternative thread over in OD but I think this chemical deserves a mention over here. I've never used Tramadol myself and the only opiate/opiod I have experience with is codeine (kratom too, but I don't really count that).

I am however, VERY interested in different kinds of nootropics and non-neurotoxic SRA's that are more stimulating than the current SSRA's (MDAI, MDAT).


Here's what I posted in the other thread:

The closest thing I can think of to Tramadol that doesn't hit the μ-opioid receptors is Indeloxazine. Looking at the Wiki:

Indeloxazine (Elen, Noin) is a so-called cerebral activator used in Japan for the treatment of cerebrovascular disease.[1] It was launched in 1988.[2] Indeloxazine acts as a serotonin releasing agent and norepinephrine reuptake inhibitor.[3] It also acts as an NMDA receptor antagonist.[4] It enhances acetylcholine release through indirect activation of the 5-HT4 receptor.[5][6][7] Indeloxazine has nootropic,[8][9][6][7] neuroprotective,[10][11][12][13] anticonvulsant,[14] and antidepressant effects.[15][16][3]

Compare this to Tramadol:

Tramadol acts as a μ-opioid receptor agonist,[48][49] serotonin releasing agent,[6][7][8][9] norepinephrine reuptake inhibitor,[49] NMDA receptor antagonist,[50] 5-HT2C receptor antagonist,[51] (α7)5 nicotinic acetylcholine receptor antagonist,[52] and M1 and M3 muscarinic acetylcholine receptor antagonist.[53][54]

I've been wondering how to get a hold of some of this for a while as I love trying out different nootropics.
I also love the anxiolytic/AD and pro-social effects of Selective Serotonin Releasing Agents but thing they could do with a bit more of a "push". NE uptake inhibition might do this (minus the euphoria) without the neurotoxicity of dopamine release.

I've never used Tramadol though, although I'll be getting some as soon as I get back to Uni.

Does anybody have more info on this chemical? Potential for 5-HT2B agonism? Potential opiate combo that doesn't risk causing seizures? (As it seems tramadol has a massive marmite style fan base)... Maybe someone has tried it?

 

[Phener]

It looks a rather sexy starting block to explore further

 

[El_Toro]

Yeah, I was surprised with the NMDA antagonism too. It looks a very promising substance, I'll keep an eye on this one. I find it interesting that the Wikipedia entry claims it has anticonvulsant properties.

Is it available online? Not asking for sources but would like to know if it is exclusively limited to the Japanese market.

I am a big fan of Tramadol (not the converted o-desmethyl version). Out of all the serotonin based AD's, I would say it is the more effective although it comes at a cost (addiction, harsh WD's, possible neurotoxicity from long term administration etc).

 

[Hammilton]

anyone with chembio3D on hand who can compare that to the MDMA / AMP / and whatever the indene analogue of MDMA is called? it looks like the amine function could be positioned very similarly.

I know that vecktor had speculated about non-phenethylamine derivatives with various changes that would get the amine in the same position relative to the phenyl ring as the phenethylamines. I hadn't realized that anything similar had actually made it to market. Could release SE by a completely different mechanism and make the comparison moot, but it's worth doing a quick overlay.

 

[Poodles!]

I've been been doing a little more scouting on the interwebs and come across a few interesting studies.

It seems that it may have some nootropic qualities that are more effective than Piracetam or Aniracetam with Antidepressant effects similar to that of the TCA Amitriptyline (but probably faster acting on the account of being an SRA).¹

I'm not liking the fact that it may suppress dopamine function as nothing works better for me than increased dopamine levels for improving my motivation (of which I have little these days )²... or perhaps it doesn't?³. I'm assuming it suppresses it in certain areas of the brain and increases it in others. I'm guessing this wouldn't be much of a problem if used alongside my normal nootropic regimen, which is usually a short selegiline stint with DLPA and racetams (usually aniracetam which stimulates dopamine release in the prefrontal cortex, basolateral amygdala and dorsal hippocampus anyway) supplements. I'd hope this wouldn't add neurotoxicity to the mix as is typical of (S)SRA's alongside significant dopamine release.


I've also always associated NMDA antagonism with memory impairment.
But then I always associated serotonin release with (minor) memory impairment too (like with MDMA). Although I've always felt a sense of clarity and focus with MDAI (probably due to anxiety relief), yet noticed no memory impairment (I've only used up to 100mg of the brown stuff) with MDAI.


¹ http://www.journals.elsevierhealth.com/periodicals/cuthre/article/PII0011393X95850139/abstract
² http://www.ncbi.nlm.nih.gov/pubmed/2611822
³ http://www.ncbi.nlm.nih.gov/pubmed/7541089

 

[dread]

anyone with chembio3D on hand who can compare that to the MDMA / AMP / and whatever the indene analogue of MDMA is called? it looks like the amine function could be positioned very similarly.

I know that vecktor had speculated about non-phenethylamine derivatives with various changes that would get the amine in the same position relative to the phenyl ring as the phenethylamines. I hadn't realized that anything similar had actually made it to market. Could release SE by a completely different mechanism and make the comparison moot, but it's worth doing a quick overlay.

Lol, I thought the same thing when I saw the molecule...

 

[Hammilton]

I overlayed them. It took me some trouble to get them aligned right (with MDMA though) and they're decently well actually. Not great, but accounting for the greater flexibility of indeloxazine, you can easily see them binding to the same site.

 

[atara]

Sounds recreational as hell. Is there a SAR for this type of thing? It doesn't look like any other serotonin releaser I've ever seen (though I know it *overlays* MDMA, thanks Hammilton)

 

[Hammilton]

I would like someone here with more experience with these manual overlays to give it a shot too. I could have done something wrong. Actually I'll post my overlay in a minute.

 

[Hammilton]

I was just about to post it, but I had to redo it, and the results I'm getting now are worse than before. Before I'm sure all of the numbers were less than 1.25A --> but now I'm getting decent numbers for other atoms, but the amine groups are 2.5A apart

 

[/navarone/]

Have you tried with both isomers? (check the morpholine ring )

 

[Slapdragonx]

Wow. Would the amine group line up correctly?

 

[mgrady3]

lol. but potentially not a lol.
the second google hit on the chem....
that picture is just silly.
(sorry if this is too close to sourcing)

 

[TheAzo]

The comparisons to MDMA et al have two flaws IMO...

1) the closest amphetamine is not MDMA, but 6-APB. Which, as we all know from following the 6-APB threads, kinda sucks, and losing the oxygen in the 5-membered ring is unlikely to improve matters any.

2) the analogy is only relevant if the stuff hanging off the ether is pointed in one direction, so it will often not be in the binding conformation. The whole thing depends on it curving around to put the amine in the same spot! Plus, who knows how the receptors will feel about that oxygen in the morpholine ring.

3) It doesn't release DA, and is only an NE reuptake inhibitor, so to get MDMA-mimetic effects you'd need to throw something else in.

4) Have you all learnt nothing from 5-IAI and 6-APB? Triple releasers do not all act as empathogens! Simple triple release is not sufficient. What things _ARE_ good empathogens, and are also well studied? All you have is MDMA and it's close relatives, and aMT/aET (and neither of those are as good as MDMA). MDMA is known to act as an HT1A agonist, which triggers the release of oxytocin (which is associated with feelings of trust and love - hey, isn't that the magic of MDMA too?). And aMT is a direct serotonin receptor agonist; it's listed as non-selective, but who knows how non-selective that is. I claim that HT1A agonism is the missing ingredient in all these MDMA replacements. And this compound doesn't look like it's got it (they appear to have looked at some pretty obscure receptors, so you'd think they'd have found it if it had it)
Not that I don't think this compound looks interesting, and not that i wouldn't be averse to trying it, but I don't think analogizing it to MDMA at this stage is really reasonable.