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Aptiganel

nuke

nuke

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Nov 7, 2004
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A thread for this compound.

Aptiganel is a non-competitive NMDA antagonist.
It has a four hour mean plasma half life in humans.
It passed mammalian assays okay and made it to clinical trials in humans, where it anchored because it failed to prevent complications of stroke while having side effects such as sedation, elevated pulse rate and hallucinations.
Active dose in humans is 1-3mg IV (unknown oral).
Not currently scheduled.
 
I am very interested...

Aptiganel.png


Hmm... Doesn't remind me of anything in particular...
 
They seem to be inclined to produce nasty effects (sometimes fatal) - things like nomifensine (the nomifensine derivatives without an aromatic NH2 group seem fairly safe, if a fair bit less effective as an antidepressant). Add to that the fact that a shit loads of aromatic amines are horribly toxic and it settles it for me. I know things like folic acid, which is essential, contain para-aminobenzoic acid amino group attached at the 4 position of the benzene ring, it just seems man made drugs with an aromatic amine group are generally nasty

(just treat me as having irrational views about certain drug structures that I drew my own warped opinions about :) )

The top part of the molecule is effectively an imine of alpha-naphthylamine - imines aren't the most stable of compounds (they hydrolyse fairly easily) and if you look at the MSDS for 1-naphthylamine, it's pretty nasty stuff
 
I haven't seen anyone anywhere in the chem market provide this. Looking at the patent for this and other diphenylguanidine nmda antagonists they seem easy/cheap enough to produce altho some have low yeilds. aptiganel had strong dissociative effects in humans and didn't protect against stroke so it was nixed. I've wanted to try this for a while.
 
Aromatic Amine?This is a guanidine man =D

There are some antihypertensivas like Guanabenz (funny name...) which even is a hydrazide (not that it has any other similarities with Aptiganel):

http://en.wikipedia.org/wiki/Guanabenz

Well its a bit like a guanidinized mothball version of Lefetamine but don't look too closely ...
 
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Actually I second that somehow...the bias is not completely irrational, as the concerns about the toxicity of anilines is not far-fetched...
 
I also concur about the general sketchiness of the aromatic amine (in this case, the aromatic imine is what I would be worried about). While I doubt one dose would be too dangerous, I do enjoy my liver, so I'm not too keen on attacking it with possible toxins.
 
If it was tested by pharma in humans, probably old geezers at that. I could be wrong but I would assume that this compound and compounds similar were established to be pretty safe no?
 
The noncompetitive glutamate antagonist, Cerostat/Aptiganel, appeared to have more favorable pharmacokinetic properties. The CNS effects of the drug were apparent within minutes of commencing infusion, confirming rapid penetration to the brain, and in the event of excessive side effects, infusions could be discontinued with resolution of the effects after at most a few hours [78, 79]. Nevertheless, a similar constellation of side effects was encountered with Aptiganel, namely sedation, nystagmus, hallucinations, and in extreme cases a transient catatonic state. These symptoms limited dosing once again, but plasma concentrations in the range of 10–12 ng/mL were achievable in stroke patients, on the threshold of those that were associated with neuroprotection in rat models of stroke [80, 81]. Aptiganel was explored in a small phase IIa study in stroke patients before proceeding to a phase IIb/III trial. This trial was abandoned at the first planned interim analysis on the basis of apparent futility.
Click to expand...
http://mrw.interscience.wiley.com/emrw/9780470101001/hcn/article/hcn058/current/html

I imagine that the animal tox couldn't have gone too poorly if it made it to phase III clinical trials. The doses administered to rats were much higher than those given to humans, too.

All of the side effects seem to indicate PCP or ketamine-like activity.
 
Question: Why is the anaesthetic's failure to produce a beneficial side-effect (protection against eschemia) causes it to be halted? Is anti-eschemic activity a prerequisite for a useful anaesthetic?
 
These were developed as inhibitors to the toxicity produced by ischemic cascades, not as an anaesthetic. Very high doses of NMDA antagonists tend to do this in animals, but they've had trouble reproducing those results in humans.

Here's the full-text of the halted human trial: http://jama.ama-assn.org/cgi/content/full/286/21/2673
And the safety and tolerability trial: http://stroke.ahajournals.org/cgi/content/full/strokeaha;30/10/2038

The drug was developed as an acute response to stroke, so long term toxicology studies in rats may not have been required to pursue human clinical trials (I'm not entirely sure how it works).

edit: Here's the synthesis paper from the journal of medicinal chemistry too: http://www.ncbi.nlm.nih.gov/pubmed/8295213

I'm not too concerned with the guanidine group because melamine seems mostly to not hurt human adults. I wouldn't take it often though. Heterocyclic amines are also a commonly formed during the cooking of meats (not that it makes them all that much safer).
 
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again use this reasonably infrequently and I would have to gather it is quite safe...chronically may be another issue, but even that may not be an issue

it was not abandoned for toxicity or related issues, but because it produced the side effects of a negative nature that those herein are looking for as the main effects :)
 
actually it was abandon because it failed to protect against stroke. diphenylguanidines in general have very strong effect on pcp receptors (some are more potent than mk801) but most have about atleast 1/2 that potency toward NMDA and some are pimarily sigma agonists. aptiganel is a good middle ground for all those making it a recreational potential so I don't think they'd bother making it available as an aneasthetic as there are plenty of those out already with pressumably less "hallucinogenic" properties and are shorting acting(ketamine). Sometimes side effects be it recreational or negative are tolerable depending on what the drug is treating.
 
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