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Are there any good SNDRIs yet?

Never thought anybody would seriously consider DXM+bupropion for approval as I discovered this combo by accident while taking 150mg bupropion SR (lowest available dose) and 2x 50mg DXM HBr SR (recommend daily dose for cough) and with strong recreational effects. It *is* a potent antidepressant, yet also a dissociative - I remember to borderline-hole at least twice without warning and while in conversations. To somebody without disso experience such a state might be pretty frightening. Needless to say, I happened to like it and continued to with the DXM for a month or so when I stopped because of uncertainity about physical safety. My left-ear tinnitus increased heavily in intensity and just one can of energy drink felt like some cathinone.. No other side effects to remember though, so if the tinnitus thing would go away after getting used to the drugs I would consider to use it again and certainly as feeling less toxic than some approved medicines - knowing this is no criteria for approval. Oh, and the increase in energy is *huge*. Different from the amphetamines, more wakefulness and physical energy (NE?) and less anxiety as far as I remember.

Wish them good luck though, will be a thing to pass abuse trials, even with DXM alone today .. How are such ones done anyways? By feeding lever pressing, sensorically deprived rhesus monkeys, former drug addicts or drug - naive individuals and asking them if they "liked" the drug and "would use it again"? Guess I fear the latter, or any of these, which would give dysphoric drugs a huge bias..

polymath said:
The late 1990s "DXM FAQ" claimed that DXM also inhibits DA reuptake, similar to bupropion, but no present-day source seems to say the same.
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Probably as you say it's wrong. Curious though as it appears to be not just some wild speculation but based on PCP binding sites and never heard of that being a potent NRI. Might be though and they just mixed up NRT and DAT?
 
So they're gonna combine DXM and bupropion? Are we going back to the age of those crazy combo meds? Surely this if you want a drug with nmda antagonism + NDRI qualities there are plenty to explore? We've only scratched the surface with dissos.

I suppose the thinking is that it's easier to get approval using two drugs that are already in circulation?
 
For approval, pretty much because they are already in circulation and both in combination meds, including one with a similar pharmacological mechanism that can be highlighted.

Besides both being fairly established, each was used in other formulations. Bupropion was approved in bupropion/naltrexone for obesity. DXM was approved in DXM/quinidine for pseudobulbar affect, with a relevant pharmacokinetic interaction (CYP2D6 inhibition by quinidine, similar to bupropion). Hope for efficacy from pharmacological interactions and watch for any emergent safety signals (I think bupropion can even lower QT compared to say the quin/dxm combo).

Then follow it up with an enantiomer of bupropion so people can't just get the components separately, e.g. buying some DXM polisterix when you are taking bupropion.

Combo meds that have failed, not including safety signals and less efficacy, surprises beyond what initial lab and phase II early III, usually fall under not providing a unique justifiable drug reason, a la failed leukotreine inhibitors / antihistamine combos. Some of the antihypertensive combos got passed due to compliance/convenience and some amount of additive effect, same with inhalers.

I've been waiting on more combos again since I got this fabulous Takeda bag for contrave. Gotta have the companies cooperate though.
Ykqtpfw.jpg
 
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bupropion enantiomers are a waste of time they epimerise faster than you can say compounding pharmacy.

I remember when Takeda was a proper drug company, justifiably famous and widely recognised for ballsy moves on pharmaceuticals, betting the farm not once but twice in the 80's and 90s on promising lead compounds.

Takeda should not be famous for lame nylon bags, though it has to be said this ugly purple bag has left a lasting impression with some people.
 
Oh it is a hideous bag - was being more cheeky. Fabulous more in the obnoxious sense. I should make that more clear, especially with the fact that it was given out in a PCP's office with a measuring spoon.

Well, Takeda suffered with that actos situation, between the bladder Ca questions and HF. Even though it wasn't same as rosiglitazone, perhaps hiding some of the risk evaluation and data. Though it still seems higher reaction by some authorities than actual risk. Remember that more than purple bags...and I take one of their drugs. Was more excited for their CNS/neuro pipeline in the past

Looking to see more with the Shire merger.

I thought the epimerization may have been less under some physiological conditions. Still not a great choice.
 
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biolabile linker between DXM and bupropion to give a comination drug give you a NCE which is patentable.
 
Well well well, noetic branching dose'nt half come up with some revelry, it's simple, if you want it on a dopeminigeuc noetic scale, take three,then two, then take three.then take two, bravco, lechin, emscot, deangate, gienecology department,'now'
, mash up.
 
I imagine at higher than usual doses, perhaps approaching danger, DXM does bind to and block DAT
 
raising_da_piggy said:
Well well well, noetic branching dose'nt half come up with some revelry, it's simple, if you want it on a dopeminigeuc noetic scale, take three,then two, then take three.then take two, bravco, lechin, emscot, deangate, gienecology department,'now'
, mash up.
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QFT
 
(±)-McN 5652 (US Patent 6,162,417 by Goodnam and Shi) is an interesting one. https://doi.org/10.1021/jm00391a028 covers the class. You will no doubt have spotted the similarity to nomifensine & diclofensine. I suppose I will never get to try out other ring substituents, still, to quote from the paper:

Page 1443, paragraph 1:

Indeed, the 4’-chloro (22b,McN-5292) and 4’-amino (52b, McN-5908) derivatives are more potent antagonists of NE uptake than desmethylimipramine (DMI), the 3‘,4’-dichloro (29b, McN-5532) and 4‘-amino (52b) derivatives are more potent inhibitors of DA uptake than amfonelic acid, and the 4’-methylthio derivative (48b, McN-5652-2) is a more potent inhibitor of 5-HT uptake than sertraline (see Table IV).21 Acetamide 53b is exceedingly potent in the TBZ assay, yet it does not show exceptional neurochemical activity; thus, 53b may be a prodrug for 52b.
 
clubcard said:
(±)-McN 5652 (US Patent 6,162,417 by Goodnam and Shi) is an interesting one. https://doi.org/10.1021/jm00391a028 covers the class. You will no doubt have spotted the similarity to nomifensine & diclofensine. I suppose I will never get to try out other ring substituents, still, to quote from the paper:

Page 1443, paragraph 1:

Indeed, the 4’-chloro (22b,McN-5292) and 4’-amino (52b, McN-5908) derivatives are more potent antagonists of NE uptake than desmethylimipramine (DMI), the 3‘,4’-dichloro (29b, McN-5532) and 4‘-amino (52b) derivatives are more potent inhibitors of DA uptake than amfonelic acid, and the 4’-methylthio derivative (48b, McN-5652-2) is a more potent inhibitor of 5-HT uptake than sertraline (see Table IV).21 Acetamide 53b is exceedingly potent in the TBZ assay, yet it does not show exceptional neurochemical activity; thus, 53b may be a prodrug for 52b.
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you aint dead I did wonder! have you still got limpet chicken locked in your basement?
 
novaveritas said:
you aint dead I did wonder! have you still got limpet chicken locked in your basement?
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Serious health problems, mate. Seizures, broken pelvis, failure of hip replacement (and not enough bone to redo) . Dunno about LC but he always seemed angry.

In other news - pyrazolam, pynazolam & pyeyzolam are being patented by Alcorelle. The inventors are listed as Professor David Nutt and another guy...:)
 
clubcard said:
Serious health problems, mate. Seizures, broken pelvis, failure of hip replacement (and not enough bone to redo) . Dunno about LC but he always seemed angry.
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Hip problems are a real pain in the ass, I had an inflammation in my hip joint some years ago and then next winter I had a small fracture in there after falling on ice. And I'm not even 40 yet.
 
Bravoncius Roxford said:
cocaine, the "prototypical" SNRDI inhibitor is not really a SNDRI, but rather a drug that has many different enantiomers, with some having more affinities for one transporter over the other 2.
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Many homologs and analogs, but original cocaine nigh always is the closest to evenly nonselective between all three transporters. It's stereoisomers are all unaffective as SNDRIs: i.e. R-cocaine, the one naturally found in erthroxylon coca (sp), is the only active one.
 
polymath said:
Hip problems are a real pain in the ass, I had an inflammation in my hip joint some years ago and then next winter I had a small fracture in there after falling on ice. And I'm not even 40 yet.
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Yeah - ended up in hospital for months, got discharged with an oxy script and it's official - I HATE oxy. GP decided I didn't need analgesia so I'm very much DIYing that issue. It's a bitch but I'm sure I don't need to tell YOU that, do I. I'm still mobile using crutches but will end up in wheelchair sooner or later which I do not fancy... t

Still, name on patent for alcohol mimic along with Nutt. Of course, we can make a 'drunk' pill but since then, I've figured a second site that low dose ethanol binds to so can mimic 2 beers.
 
The one sekio gave the 2D for reminds me of that reuptake inhibitor benzo, a 2,4 benzo?

Thing with a 'good' SNDRI is that in vitro type spread of affinity for each won't tell how subjective it will feel, as studies have shown again and again. What conformation the ligand locks MAT into when docked is a better indicator of use or euphoria.
 
Anybody have good binding affinities for the major antidepressants?
 
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