Zolpidem possible Cholinergic effects?

[Lightning-Nl]

Happened to be doing some research on Zolpidem and after a quick scan of the molecular structure of Zolpidem I noticed this...

I don't know what this structure is called so excuse my ignorance. However, I happen to notice this Nitrogen-carbon bond on many Cholinergic effecting substances and any substance that has this structure, also seems to be antimuscarinic or is a nicotinic agonist.

So I did some light research and happened to come up with this study. This study measured the effects that nonbenzodiazepines (zolpidem and eszopiclone) has on cholinergic activity. As a control, they used another GABAergic drug which was Diazepam. They found that...

ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam.

Interesting.

nAChR-7's structure is very similar to that of the GABA receptor. Ethanol which isn't related in molecular structure to Zolpidem in anyway, interestingly enough, binds to and agonizes nAChR-7.

Is it possible that Zolpidem might possibly bind to nAChR-7 and also agonize the receptor? What's your guy's thought on this?

 

[sekio]

I don't know what this structure is called so excuse my ignorance. However, I happen to notice this Nitrogen-carbon bond on many Cholinergic effecting substances and any substance that has this structure, also seems to have antimuscarinic or is a nicotinic agonist.

it's called an amide, and it's a very common chemical motif.

 

[Lightning-Nl]

it's called an amide, and it's a very common chemical motif.

Fair enough. I know what an amide is, but until I looked it up just now, I didn't understand exactly what it was. Since 95% of my understanding of chemistry and drugs is self-taught, my knowledge on the subject is sporadic. I can explain some advanced concepts of drugs, human behavior and chemistry and have no idea what something simple like this is.

Anyways, my idea that Zolpidem could bind to the nicotinic acetylcholine receptors isn't ludacris, wouldn't you say? I know that GABA release inhibits transmission of ACh, but if Zolpidem really does bind to nAChR, that wouldn't really matter right?

 

[Hammilton]

I don't think it does. Increasing. Acetylcholine release isn't the same as receptor agonism.

 

[Lightning-Nl]

My mistake. I learned that a while ago, but I still subconsciously write that into my posts.

Let me refrase that. Do you think this release of ACh, that zolpidem causes, could be what causes Zolpidems "sleep walking" effects?

 

[sekio]

I doubt it; the amnesic effects from its effect at some subunits with benzodiazepine receptors is a more likely cause. People do funny shit like sleepwalking when their short term memory is supressed.

As far as I can tell, nobody has reported zolpidem having any affinity for nAChR. Nicotinic antagonists are probably better paralytics. than memory suppressants.

However - There's a curious bit of overlap between nicotinic antagonists and NMDA receptor antagonists - known antinicotinic compounds are e.g. memantine, amanitidine, DXM/DXO, ibogaine and its relatives. I think PCP/ketamine/MXE are probably the same.

 

[Lightning-Nl]

I doubt it; the amnesic effects from its effect at some subunits with benzodiazepine receptors is a more likely cause. People do funny shit like sleepwalking when their short term memory is supressed.

As far as I can tell, nobody has reported zolpidem having any affinity for nAChR. Nicotinic antagonists are probably better paralytics. than memory suppressants.

However - There's a curious bit of overlap between nicotinic antagonists and NMDA receptor antagonists - known antinicotinic compounds are e.g. memantine, amanitidine, DXM/DXO, ibogaine and its relatives. I think PCP/ketamine/MXE are probably the same.

Yes, I've noticed that as well. It's similar to how most opiates also bind to Sigma-1. Quite interesting stuff.

Anyways, I'll take your word. I'm not exactly the expert in this area. I know a lot more then the layman, but in something as vast as Pharmacology, Chemistry and Human Behavior, I still know very little.

Wouldn't you agree though, that this release of ACh is more than likely what causes nonbenzodiazepines slightly dizzying effects? I guess it could be attributed to GABAa modulation, but Benzodiazepines don't make people dizzy....well, at least I don't anyways...

 

[sekio]

Nope, it's probably GABA-a positive modulation. Dizziness and confusion is a documented side effect of benzos.

Benzodiazepines and the "z-drugs" are pretty damn selective.

 

[Lightning-Nl]

Nope, it's probably GABA-a positive modulation. Dizziness and confusion is a documented side effect of benzos.

Benzodiazepines and the "z-drugs" are pretty damn selective.

Good to know. Thanks.

 

[Limpet_Chicken]

Sekio, as far as paralytic agents go, that is dependent on the binding site being the neuromuscular junction. In the case of either an antagonist (such as curare, a non-depolarizing neuromuscular blocker derived from species of Strychnos plants), or an agonist that binds and activates NAChRs but is either not degraded by cholinesterases or is very poorly degraded (depolarizing neuromuscular blocking agent, example-succinylcholine) these work by activating the receptor until it is essentially fatigued and cannot recover due to lack of clearance by cholinesterase, resulting in first muscular fasciculation and then subsequent paralysis.

Or the odd, and far less common agents such as botulinum toxin which inhibits ACh release, or alpha-latrotoxin, from the venom of Theridiid spiders in the genera Latrodectus (the true widow spiders...incidentally beautiful spiders, I used to have a pet brown widow spider actually ), Steatoda (false widows) and probably, although I haven't actually looked into it, Parasteatoda spp. also.

The latter causes continuous; massive release of acetylcholine, resulting in severe nausea, vomiting, twitching, muscle fasciculations, potentially the shits, severe muscle stiffness, cramping all over, and severe pain. Everything one would expect from exposure to a military nerve agent, basically.
End point in severe intoxication is at first rigid then later flaccid paralysis.

Having been bitten by Persephone once when she got pissy with me cleaning out her enclosure, I can verify that lot as accurate, although the intoxication was not at the dangerous end of the severity scale, but it was HIGHLY unpleasant, and left me aching all over, like I just had a cricket bat-wielding bull elephant leather the everloving shit out of me. Thankfully she was a brown widow (Latrodectus geometricus) rather than one of the black widow varieties, and as such, delivers less venom than do the other latros.

No paralysis, but some neuromuscular symptoms. Fucking horrible experience though. I'm just glad I didn't react instinctively to being bitten by bringing down the great big hammer-hand of doom and hurting her in return; I couldn't hold sepphy responsible for a defensive bite.

 

[Lightning-Nl]

Sekio, as far as paralytic agents go, that is dependent on the binding site being the neuromuscular junction. In the case of either an antagonist (such as curare, a non-depolarizing neuromuscular blocker derived from species of Strychnos plants), or an agonist that binds and activates NAChRs but is either not degraded by cholinesterases or is very poorly degraded (depolarizing neuromuscular blocking agent, example-succinylcholine) these work by activating the receptor until it is essentially fatigued and cannot recover due to lack of clearance by cholinesterase, resulting in first muscular fasciculation and then subsequent paralysis.

Or the odd, and far less common agents such as botulinum toxin which inhibits ACh release, or alpha-latrotoxin, from the venom of Theridiid spiders in the genera Latrodectus (the true widow spiders...incidentally beautiful spiders, I used to have a pet brown widow spider actually ), Steatoda (false widows) and probably, although I haven't actually looked into it, Parasteatoda spp. also.

The latter causes continuous; massive release of acetylcholine, resulting in severe nausea, vomiting, twitching, muscle fasciculations, potentially the shits, severe muscle stiffness, cramping all over, and severe pain. Everything one would expect from exposure to a military nerve agent, basically.
End point in severe intoxication is at first rigid then later flaccid paralysis.

Having been bitten by Persephone once when she got pissy with me cleaning out her enclosure, I can verify that lot as accurate, although the intoxication was not at the dangerous end of the severity scale, but it was HIGHLY unpleasant, and left me aching all over, like I just had a cricket bat-wielding bull elephant leather the everloving shit out of me. Thankfully she was a brown widow (Latrodectus geometricus) rather than one of the black widow varieties, and as such, delivers less venom than do the other latros.

No paralysis, but some neuromuscular symptoms. Fucking horrible experience though. I'm just glad I didn't react instinctively to being bitten by bringing down the great big hammer-hand of doom and hurting her in return; I couldn't hold sepphy responsible for a defensive bite.

Sounds exactly like when you smoke too many cigarettes, too fast. You literally feel like death, with all the symptoms you described above, for 10-15 minutes. I imagine that yours lasted quite a bit longer, which I couldn't even fathom going through.

Anyways, when those awful "Nicotine overdoses" occur, I just quickly crush up a Benadryl and take it. Usually offsets the Nicotine fairly quickly.

 

[Limpet_Chicken]

Aye, it was most unpleasant.

Similar experience to nerve agent poisoning, unsurprisingly (no, I haven't been using the lab to cook up military nasties like tabun, G, V, GV or novichok series agents)

Although the nerve agent exposure was far, far worse. The widow bite lacked most of the SLUDGE symptoms, surprisingly.
Just imagine getting ganged up on by about 20 great big fucking meathead thugs with various instruments of blunt force trauma, and being worked over until you feel like you've gone and had it for good. And having to explosively puke and shit, whilst your stomach and abdominal walls are so damn stiff you can't toss your cookies, just, stuck there subjected to reverse peristalsis of the most immediate, and brutal kind.

And for days afterwards, I could just BARELY hobble about, legs, back, torso, etc. all were stiff as concrete and unbelievably painful, aching, twinging, twitching not wanting to move voluntarily. I can only compare it to what having one's bones replaced with red hot cement, whilst being connected to the home electric mains supply. By the bollocks.

Not to mention nose, eyes and mouth streaming like someone turned a hosepipe on full blast. I was sticking my former housemate's left behind, unused (obviously ) tampons up my fucking nose, to avoid feeling like it was going to leak back down and drown me. Felt stiff as a stack of wooden planks afterwards though whilst recovering.


The spider bite lasted a couple of days, the latter nasty experience almost a week (the acute effects, I was.
Lets just say, that by the end of that horror, I was fucking glad to get my scripts from the doc, and shovel a fuckton of opiates and benzos down my neck!

 

[ebola?]

Anyways, when those awful "Nicotine overdoses" occur, I just quickly crush up a Benadryl and take it. Usually offsets the Nicotine fairly quickly.

I don't see how this could be effective, as the nicotinic and muscarinic ACh receptors are quite distinct, nicotine and diphenhydramine being pretty selective for each one. I also think that oral or sublingual administration of diphenhydramine couldn't work sufficiently quickly, the nicotine being catabolized on its own.

Similar experience to nerve agent poisoning, unsurprisingly (no, I haven't been using the lab to cook up military nasties like tabun, G, V, GV or novichok series agents)

Good call. "Ooops, I poisoned the entire neighborhood. . . ."

ebola

 

[Lightning-Nl]

I don't see how this could be effective, as the nicotinic and muscarinic ACh receptors are quite distinct, nicotine and diphenhydramine being pretty selective for each one. I also think that oral or sublingual administration of diphenhydramine couldn't work sufficiently quickly, the nicotine being catabolized on its own.

It lowers overall levels of Acetylcholine. I know it's antimuscarinic, but the with nothing binding to the muscarinic receptors, that (I'm assuming) levels out ACh. I don't get it either, but it definitely works - especially if you accidentally swallow Nicotine gum. If you ever have the misfortune of doing that......god help you.

 

[sekio]

"Ooops, I poisoned the entire neighborhood. . . ."

Whoops, my house is a Superfund site. There are no birds here any more.

 

[ebola?]

It lowers overall levels of Acetylcholine

No, we're talking about direct agonists and antagonists--ACh levels remain roughly similar to what they were.

but the with nothing binding to the muscarinic receptors, that (I'm assuming) levels out ACh.

I don't understand what you're saying here. Could you elaborate?
...
Anyway, this is not how we should think about acetylcholinergic transmission; muscarinic and nicotinic effects are quite distinct and don't really add up to some coherent 'sum activity'.

ebola

 

[SpunkySkunk347]

what about this about zolpidem: indirectly agonizes 5-ht2a pathways, fact or myth?

 

[ebola?]

I haven't heard of research demonstrating such, and SAR doesn't suggest anything of the sort.

ebola

 

[Lightning-Nl]

what about this about zolpidem: indirectly agonizes 5-ht2a pathways, fact or myth?

Very unlikely, but it hasn't been proven to be true (as far as I know).

More than likely, the hallucinations caused by Zolpidem are due to the fact that Zolpidem crosses into the peripheral nervous system. This probably agonizes GABA in the optic nerves, thus "inhibiting" the eyes. This is probably what cause the hallucinations caused by Zolpidem. (Hope I explained it correctly)

 

[ebola?]

I severely doubt that. My best guess would be that zolpidem causes hallucinations through the same mechanism that lorazepam occasionally induces such (in particular individuals), albeit much more prominently, so we should look to the alpha1 subunit of the GABAA receptor, for which zolpidem is highly selective over other subunits.

ebola