Milnacipram Naphthyl Analogue: Triple Reuptake Inhibitor AND NMDA Antagonist?!

[SeenSoFar]

OK, so I cannot confirm the NMDA antagonist part of the story because I don't have full access to the paper, I only have our unreliable friend Wikipedia to go on. If someone could provide me with the full paper it would be greatly appreciated. I can confirm however that this is in fact a triple reuptake inhibitor.

So, here's the real question. Does anyone have any doubt that a triple reuptake inhibitor and NMDA antagonist all rolled into one would be anything less than incredibly abusable? What are people's thoughts on this?

Synthesis of enantiomerically pure milnacipran analogs and inhibition of dopamine, serotonin, and norepinephrine transporters​

A series of Milnacipran analogs with variation in the aromatic moiety were prepared in high enantiomeric excess. Structure–activity relationships for two parallel enantiomeric series are described. The (−)-(1R,2S)-naphthyl analog (8h) showed the highest potency in the two series and is a triple reuptake inhibitor of the SERT, NET, and DAT.​

EDIT: Funnily enough, this compound also fits the morphine rule, and it's 3D structure is also a perfect fit for an opioid. Wouldn't that be just about the most recreational compound on the planet, a triple reuptake inhibitor, NMDA antagonist, and opioid? A speedball in a single compound, with some dissociative thrown in for good measure... I think I need to change my pants...

EDIT 2: I made an error drawing this molecule since I drew it before getting to view the full paper. I have replaced the skeletal formula at the top of the page with the correct one.

 

[Jonneh]

The Wikipedia lead appears to be correct. I would guess that there would be no occlusion of effects on extracellular serotonin by the SRI and NMDA antagonist actions, since the latter changes are induced by systemic, and not local, administration of NMDA antagonists, and in the former case, local application is sufficient. I suppose this is known, or hinted at, from combinations, but I haven't looked. And who knows what direct effects this thing might have on serotonin and dopamine receptors, a la ketamine/PCP.

Anyway, yes, it could be brutal.

 

[:DNA]

not sure what this forum's policy is on rehosting files, but on the off-chance it's allowed, I'll just go ahead and post this up. Mods feel free to delete/edit this as necessary.

https://www.sendspace.com/file/oht9dg

hope this helps!

 

[blueberries]

I'm going to have to play the devil's advocate here. As much as I'd love you to be correct (also, I don't have much scientific knowledge to back up these claims), I think it would be a simple anti-depressant in the end. I assume we're talking about the (-) enantiomer here?

Also it's lack of DAT affinity worries me in comparison to the very high NET affinity. This would make it a fairly selective stimulant without much reward. If what you say is correct about the opioidergic content then I guess this would balance it out but I just don't see it being an opioid. It's structure bears resemblance to the Isoquinolines (granted minus the amine) and some of these can be quite pharmacologically active but another thing that worries me is the fact that it could be an MAOI. Also from the wiki of Milnacipran "Milnacipran exerts no significant actions on H1, α1, D1, D2, and mACh receptors, as well as on benzodiazepine and opioid binding sites."

This says a great deal about it's analogues and I doubt an extra phenyl ring would do a huge amount to alter these actions. Even more that NMDA antagonism comment is really vague. However the paper does state that Milnacipran has weak NMDA antagonism. If this could be raised and more tests were done then I'd be a lot more excited but the annoying fact is that the paper suggests that their main goal was to search for a better NMDA antagonist and they don't even have the IC50 values for NMDA there (EDIT: disregard this, it was ref. 18-22 that decided to look for this, just trying to get info on them now).

I hope you're right, I really do (in fact last night I was referring to it as the 'God compound'!) but from my (now sober) point of view it looks like a simple anti-depressant with too little DAT inhibition to be recreational and not enough information on the opioid and NMDA affinities for me to get behind it.

If anyone has more information or a different point of view please let us know as I'm watching this thread like a hawk now!

 

[blueberries]

Ok, so looking through this paper (https://mega.co.nz/#!f1c2FAAR!7sU4zBq4Tely1WLDvwMcSmjynO_SPd3eBLfNCaDwPMk), I found a compound with very high NMDA antagonism (Fig 1: 4). So i figured a hybrid between the two would be optimum for both. I could not get the papers I needed from the main paper (ref. 19-22 if anyone can help**EDIT: found them and they contain none of what I need!**) so I can't find out the IC50 values for NMDA from the original compound unfortunately.

Here are the two compounds made that are hybrids:

I think that the second would be closest to the Milnacipram analogue and the other compound but it's still a bit of a Frankenstein compound. So any thoughts would be well appreciated.

 

[adder]

Honestly, you can't just take compounds and make a hybrid, and expect it to fit no matter what. If it was so simple, then designing drugs for some targets wouldn't take years, I literally mean years. OK, the hardest part of that is recognising the nature of the site you want a compound to bind to, but still the "tuning" bit may take a very long time too. There's a multitude of ways in which a single molecule can potentially interact with a receptor, bonds have various lengths and depending on the type they're more or less flexible. There are quite a few methods of drug design, two major groups of methods are ligand-based drug design and structure-based drug design. The former relies on the structure of existing ligands, e.g. MXE can be seen as a result of the analysis of the structure-activity relationship among PCP analogues (3-MeO-PCP, PCE, and ketamine all taken into consideration). Alternatively a base structure is derived called a pharmacophore, which is then modified. One can then check how a molecule binds to a receptor and derive compounds that have higher affinity and/or selectivity or are agonists or antagonists, and so on. In the long run this is a trial-and-error method at some point, well they all are actually. Anyway, this is what people are attempting in the "Random Molecules" thread, they look at existing compounds and try creating new ones, however often not taking into consideration that different substituents have different sets of properties and that different bonds are different in nature, bond lengths and angles are also very important for predicting 3D structures (with that being said, I wouldn't change more than one variable at the same time). The structure-based drug design relies on 3D images of target receptors, one gets an image of the receptor they want a compound to bind to and then they design a ligand. The advantage here is that you get to know what residues (aminoacids) a binding site is made of and then you can modify your ligand according to that knowledge. In practice you're going to need a lab at some point anyway, but great ideas may indeed be born on paper.:D