Binding data for popular arylcyclohexamines.

[WSH]

May I ask, why block serotonine receptors? This would be a pretty easy experiment and I've actually done it before, but the dose of my serotonine antagonist might not have been high enough or it's affinity too low. It was quetiapine at 150mg and s-ketamine was used intravenously and intramuscularly both at 100mg. I did not notice any difference, but I might've very well used too little.
Quetiapine binding data according to wiki: 5-HT1A (IC50 = 717nM) partial agonist, 5-HT2A (IC50 = 148nM), 5-HT2C, and 5-HT7 receptor antagonist
If you explain why this would be interesting and whether the binding profile of quetiapine would get the job done, I could try it again next time I have some ketamine, but with a much higher quetiapine dose. I wouldn't do this unless it really seems like an interesting observation could be made because I will be experiencing some considerable akathisia on higher doses.
Also, quetiapine will block endogenous serotonin and to a small degree dopamine, so any euphoria will most definitely be attenuated even if ketamine doesn't interact with serotonin receptors at all.

It's because serotonin depletion blocks the antidepressant effects of ketamine:

Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism

So my theory is that a selective silent 5-ht1a antagonist would also block ketamine's antidepressant effects, just like serotonin depletion does.

Quetiapine however is only a partial agonist, so that wouldn't make much sense, a silent antagonist like WAY-100,635 would be much better.

 

[crOOk]

It's because serotonin depletion blocks the antidepressant effects of ketamine:

Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism

So my theory is that a selective silent 5-ht1a antagonist would also block ketamine's antidepressant effects, just like serotonin depletion does.

Quetiapine however is only a partial agonist, so that wouldn't make much sense, a silent antagonist like WAY-100,635 would be much better.

I don't quite understand. If they deplete the neurons from serotonin, wouldn't the animals still be depressed even if ketamine unfolded it's action as it usually does? I mean, shouldn't most antidepressants be stripped of their effects when serotonin is depleted? It was my understanding that while serotonin does seem to play an important role in mood regulation, there are still other important mechanisms further upstream that can cause depression to occur.

A radical measure like stripping these neurons of an important neurotransmitter like that and seeing a lack of therapeutic results after ketamine administration shouldn't really indicate that ketamine is immediately interacting with serotonergic neurons.

On the other hand, one could assume that ketamine can apparently not increase serotonin synthesis to any significant degree when it has been artificially depleted.

I have a feeling they're vastly overinterpretating their test results and can't quite claim that this is good study design. Tell me if you think I am wrong, I might be missing something, since I have little knowledge of the pathphysiology of depression.

 

[WSH]

I don't quite understand. If they deplete the neurons from serotonin, wouldn't the animals still be depressed even if ketamine unfolded it's action as it usually does?

They reduced the serotonin content from ~700ng/g to ~200ng/g and that in itself did NOT make the rats more depressed, it just eliminated ketamine's antidepressant effects.

I mean, shouldn't most antidepressants be stripped of their effects when serotonin is depleted?

Yes, MOST but NOT all antidepressants are dependent on endogenous serotonin; SSRIs, SRAs, MAOIs and ketamine ARE dependent on endogenous serotonin, but direct 5-ht1a-agonists for example are INDEPENDENT of endogenous serotonin.

 

[crOOk]

They reduced the serotonin content from ~700ng/g to ~200ng/g and that in itself did NOT make the rats more depressed, it just eliminated ketamine's antidepressant effects.

Yes, MOST but NOT all antidepressants are dependent on endogenous serotonin; SSRIs, SRAs, MAOIs and ketamine ARE dependent on endogenous serotonin, but direct 5-ht1a-agonists for example are INDEPENDENT of endogenous serotonin.

A direct 5-HT1A-agonist is probably working when serotonin is depleted because it mimicks serotonin itself, even if not at every receptor. I don't think such an antidepressant will ever be of significant importance in humans.

Basically they showed that those animals who had their depression simulated by being exposed to repeated stress reacted to ketamine's antidepressant effects while those with whom the serotonin depletion was used for modelling depression did not react to ketamine. It's not clear to me how this is an indicator for ketamine's antidepressant properties being dependent on serotonin and I will try to explain it another way.

The thing is that direct serotonin depletion (without any upstream process inducing it) might not even closely model depression in humans. You probably know much better than me how many aspects there are to the pathogenesis of depression and that different factors can contribute to varying degrees to whether or not an individual developes depression.

NMDA antagonists can for example be used for fear extinction in rats. You will find various studies demonstrating this (sorry I don't have much time now, but I can look some up if you want me to). Ketamine could very well interact with behaviorally acquired depression by actually reversing some of the learned behaviour (oversimplified) which would be very high upstream in the pathogenesis of depression.
Now when a mouse is not close to actually being depressed, but simply has it's depression chemically mimicked by having a monoamine neurotransmitter depleted that plays a crucial role in mood and behaviour, then maybe ketamine just cannot do much about that. There might not be any way for it to raise serotonin levels without any underlying pathological processes having ever occured.

You can see I am highly sceptical still and I really don't think the findings of this study are very hot.

 

[Toz]

If ketamine had any relevant opioid activity I would be in a world of hurt after every time I had taken ketamine which is not the case. I have been addicted to opiates for so long that even using 10mg of morphine nets me a whole week of withdrawals, yet I can use grams of ketamine for days and all I will get is cramps. It also does not feel like it has any opiate activity.

 

[crOOk]

If ketamine had any relevant opioid activity I would be in a world of hurt after every time I had taken ketamine which is not the case. I have been addicted to opiates for so long that even using 10mg of morphine nets me a whole week of withdrawals, yet I can use grams of ketamine for days and all I will get is cramps. It also does not feel like it has any opiate activity.

Haha thanks for supporting what I said about other heavy ketamine users I know who were not opiate addicts. Now with someone like you this makes the case much stronger.

Then again... Maybe ketamine acts in a way that prevents certain side effects of common opioids. I think it's highly unlikely, but don't think we can exclude it since it simply is an entirely different drug after all.

 

[blueberries]

All I know is that MXE and Ketamine are great for avoiding withdrawal symptoms after heavy opiate binges. Also what about Bromadol and 3-HO-PCP? These are both heavy opioids, this could be just the -OH on the phenyl ring but I think something much more important happens when you add an oxygen onto the benzene ring, that being mu opioid agonism. So is it the DRI or the mu-opioid agonism that causes addiction? It's like the chicken or the egg. IMO it's both and it feels great (both chicken and eggs, but not what they do in China, raw chicken fetus is just grim).

 

[crOOk]

Well if you take said Hydroxy group away from Bromadol (what's that compound called?), you'd end up with a molecule that's considerably different from plain PCP (that amine and the ethyl before the phenyl). I have a hard time believing that the two would fit into the same binding sites. Therefore, I don't see how adding the hydroxy would cause the same change either.
Correct me if I'm wrong, but it doesn't seem this sort of QSAR exists, not with the two examples you are giving here.

In my experience 3-OH-PCP feels nothing like an opioid. It was entirely lacking any psychotropic activity for me and the two other people I know who have sampled it. We had NMR and GC/MS performed by a friend at his workplace and while I cannot and did not interpret those he confirmed we had 3-HO-PCP. This stuff felt like a fucking poison and produced violent muscle clonus upon prolonged active contraction of the respective muscles. Fuck this shit lol.
I should add that we all had a massive dissociate tolerance at the time, so there might've been some psychotropic effects that we failed to see. I definitely saw NO opioidergic activity though. This is so weird:
http://www.bluelight.org/vb/threads/529288-A-trial-with-3-OH-PCP

 

[adder]

Bromadol has a hydroxy group in a completely different place from 3-HO-PCP. Bromadol has the p-bromo group on the same aromatic ring where 3-HO-PCP has the m-hydroxy. Meta substitution gives much poorer opioid affinity than para or ortho, so it's hard to say that 3-HO-PCP is an opioid at all.

Perhaps dissociative arylcyclohexanamines just potentate opioids or have some indirect opioidergic activity, but now as I'm looking at it, it simply may be NMDA antagonism that provides some relief during opioid withdrawal. Certainly different arylcyclohexanamines help to a different extent, perhaps they help in some way in opioid binding.

 

[blueberries]

I was simply going by this report from your PCP analogues page and some other peoples' experiences with 3-HO-PCE, so I'm sorry if I was not entirely accurate. Also the mention of Bromadol was simply that it's activity stems from Hydroxy bond at the para from the basic ACH stucture that has additions to (i.e the phenethyl group and the bromine).

3'-HO-PCP
Report:
Now this is a winner. 3mg of this compound taken orally as HCl salt knocked me out. This one must have some serious affinity for morphine sites because I could take less morphine. I leave it marked because its analogs may be serious opioid agonists. Officially, 3’-HO-PCP is like 10% of morphine. The only problem with this compound is that it’s 8 times as potent as PCP at PCP receptor so opioid activity (although it’s hundreds much more pronounced than with PCP) is little when compared. Yet I love this one..

 

[endotropic]

It's because serotonin depletion blocks the antidepressant effects of ketamine:

Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism

So my theory is that a selective silent 5-ht1a antagonist would also block ketamine's antidepressant effects, just like serotonin depletion does.

Quetiapine however is only a partial agonist, so that wouldn't make much sense, a silent antagonist like WAY-100,635 would be much better.

Had you seen this study? Or are you just Nostradamus?

Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test.

 

[WSH]

Had you seen this study? Or are you just Nostradamus?

Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test.

Nope, I haven't seen it before, but the pathway is just like I imagined it:
NMDA antagonism -> AMPA agonism -> serotonin release -> 5-ht1a agonism

So yes, you can call me Nostradamus if you really want to

But I'm not familiar with this novelty-suppressed feeding test, is it an antidepressant test like the forced swimming test and olfactory bulbectomy?

 

[crOOk]

But I'm not familiar with this novelty-suppressed feeding test, is it an antidepressant test like the forced swimming test and olfactory bulbectomy?

Animals are hesitant to eat food in new environments (even if the food is well known) due to the stress of being in that environment. The latency before their eating reflects the level of anxiety induced by a known stressor (the new environment). Correct me if I'm wrong. So it's not really a measure of depression.

If this is an indicator for depression, then it surely would be a much more humane test than the forced swimming test.

So even if it is (I'm not sure) a good indicator for depression and the cascade you are outlining there is correct (which seems about right), then I still don't see how that could be the central mechanism for ketamine's antidepressant effects. It probably plays a role, but just look at how purely the approved 5HT1A agonist vilazodone is doing. It really doesn't seem to do any better than ssri's.

I'm just saying, it all seems like 5HT1A plays an important role, but it surely can't be the central mechanism, can it? There must be more profound mechanisms at work here other than increasing 5HT1Ar activity. I mentioned the fear-extinction for precisely that reason. It is very remarkable that a substance can extinct fears that have been acquired days earlier. 5HT1Ar activity seems like a dead end street to me, but I might be wrong.

Upon reading the article, the novelty-supressed feeding test IS in fact, I quote from the posted article: "useful for evaluating mechanisms responsible for actions of antidepressants."

It seems that the novelty induced supressed feeding test is usually only responsive to chronic antidepressant treatment, but not to acute or subchronic treatment. (Psychopharmacology (Berl). 2007 Mar;190(4):531-40. Epub 2006 Dec 13.)
However, it has apparently been shown that ketamine and some other related substances are an exception (Iijima M, Fukumoto K, Chaki S (2012) Acute and sustained effects of a metabotropic glutamate 5 receptor antagonist in the novelty-suppressed feeding test. Behav Brain Res 235:287–292; Koike H, Fukumoto K, Iijima M, Chaki S (2013) Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. Behav Brain Res 238:48–52)

I still don't know why they would pick this test instead of testing for behavioural despair (with supressed swimming) which seems of more interest when testing for antidepressant properties or am I wrong there?

My old criticism remains btw, can other depressants show any efficacy when an AMPAr or a 5HT1Ar antagonist has been given or when serotonine has been depleted (ofc not one that is directly countering the action of the respective drug)? Some 5HT1A activity seems obligatory in order for a rat/human not to be depressed.

I think it would have been interesting to observe the rats 3 days after the drugs had been administered or the serotonin depleted.
If the rats' depression had been attenuated by then, it would've demonstrated that said mechanism cannot block ketamine's antidepressant effects completely. Granted, it's unlikely, but it could've been interesting. Unfortuntely they killed the rats 18h later to verify depleted serotonin.

The only real question that remains is why they would chose that test over checking for behavioural despair with the forced swimming test. The fact that they don't name a reason for this strikes me as odd. There have been 2 studies that have shown that the antidepressants used show an immediate response in the novelty-induced hypophagia test, but that does not seem to be sufficient reason to use it, especially since ketamine has a significantly prolonged antidepressant action compared to other antidepressants and there seems to be no need to test for anxiety over behavioural despair.
Maybe this test is more common than I think, but I'm pretty sure that I usually see the forced-swimming used in similar scenarios and it seems more appropriate when testing for antidepressant action.

EDIT: Ok, forced-swimming supposedly has poor validity (construct and face), but I'm still not sure if that's the reason for using the suppressed feeding test, since it as I stated before tests for anxiety which is not very representative for depression unlike behavioural despair.

 

[WSH]

I'm just saying, it all seems like 5HT1A plays an important role, but it surely can't be the central mechanism, can it?

5-ht1a is certainly one of the most important targets when it comes to antidepressants:

High-efficacy 5-HT1A agonists for antidepressant treatment: a renewed opportunity.

It probably plays a role, but just look at how purely the approved 5HT1A agonist vilazodone is doing. It really doesn't seem to do any better than ssri's.

My guess is that the currently availabe 5-ht1a agonists have too many limitations, like for example only PARTIAL agonism and also the paradoxical effects because of 5-ht1a autoreceptor activation.

My old criticism remains btw, can other depressants show any efficacy when an AMPAr or a 5HT1Ar antagonist has been given or when serotonine has been depleted (ofc not one that is directly countering the action of the respective drug)?

I'm pretty sure that 5-ht1a antagonism would block the antidepressant effects of most antidepressants (e.g. SSRIs, MAOIs, SRAs).


PS: It says you're from Hamburg, so let's hope for the best for your local HSV soccer team, they still have a chance

 

[crOOk]

My guess is that the currently availabe 5-ht1a agonists have too many limitations, like for example only PARTIAL agonism and also the paradoxical effects because of 5-ht1a autoreceptor activation.

Thanks for that study, I will look into that later tonight. Only read the abstract. I haven't had internet in three days (first time in 13 years lol), I gotta catch up with things.
Those are two very good points and maybe targetting this receptor directly will prove to be very effective, but I'm still sceptical that there's any proof that this is where ketamine elicits his primary antidepressant mechanism.

If the signal cascade [NMDA antagonism -> AMPA activity -> serotonin release -> 5HT1A activity] is how ketamine elicits it's antidepressant effects, then blocking this cascade at any of the three points as was done in the study will interrupt it and prevent ketamine from eliciting said effects. But if I understand this correctly, both the AMPA antagonist and the 5HT1A antagonist as well as the serotonin depletion would've inhibited 5HT1A activation anyway, in healthy and depressed rats, in rats that were either treated with ketamine or not. Please correct me if I am wrong there. If I am not, I cannot see how this is proof that the suggested cascade is what causes the magical antidepressant effect of ketamine, especially because that effect does not end with ketamine and it's metabolites leaving the body. This cascade would e.g. not sufficiently explain how the effects of ketamine can persist so long and I don't understand why this wasn't taken into account at all, as I've stated earlier.

I'm pretty sure that 5-ht1a antagonism would block the antidepressant effects of most antidepressants (e.g. SSRIs, MAOIs, SRAs).

Exactly. :D

PS: It says you're from Hamburg, so let's hope for the best for your local HSV soccer team, they still have a chance

Thanks man! I'm not really into soccer, but tomorrow will be an important day for our city for sure. Losing would be a disaster. The players only have contract for the 1st league, same goes for the sponsors, so the club would be in deep shit. 2nd biggest city in Germany without a team in the first league, that's ridiculous.

I assume you are living in Germany as well?

 

[clubcard]

The -Cl in K seems important to opioid activity. I've seen papers which showed o-methyl pethidine was more potent than it's parent. Likewise, some of the newer fentanyls have an o-substitution on the benzamide benzene.

 

[blowjay]

I don't think I have made my plug yet about how a chloro needs to be swapped in place of the methoxy in methoxetamine in this thread. Hopefully that has already happened as I have been mentioning this for the longest fucking time.

And now to make a thread due to having realized that phenobarbital and methoxetamine could create some kind of crazy monster compound if they were combined and tweaked a bit...

 

[endotropic]

I don't think I have made my plug yet about how a chloro needs to be swapped in place of the methoxy in methoxetamine in this thread. Hopefully that has already happened as I have been mentioning this for the longest fucking time.

I don't think you have either, what basis do you have for the chloro prediction?

 

[crOOk]

maybe the different subunits of nmdar (there are at least 3 i know of) interact differently or have unique splice variants.

There are three families of NMDAr subunits, GluN1, GluN2, GluN3. A receptor is usually composed of GluN1 subunits and GluN2 subunits or of GluN1 subunits with a combination of GluN2 and GluN3 subunits.

There are 4 distinct GluN2 subunits (GluN2A, GluN2B, GluN2C, GluN2D) and 2 distinct GluN3 subunits (GluN3A, GluN3B).

We currently think that at least 5 diheteromeric and 4 triheteromeric NMDA receptors are expressed in the CNS (due to 9 different combinations of the subunits). This does not take into account the heterogeneity brought on by alternative splicing.

Alternative splicing happens for the GluN1 (8 isoforms 1A-1D and 1B-4B) and GluN3 subunits (not sure about their isoforms).
The GluN1B subunit also possesses an additional amino acid stretch that is located extracellularly and apparently can be spliced differently. It's expression varies and it seems to play an important role in receptor function, e.g. pharmacological properties.

EDIT: I just realized that post I quoted is old as fuck. :D Still interesting tidbit of information.

 

[WSH]

But if I understand this correctly, both the AMPA antagonist and the 5HT1A antagonist as well as the serotonin depletion would've inhibited 5HT1A activation anyway, in healthy and depressed rats, in rats that were either treated with ketamine or not. Please correct me if I am wrong there.

Let's take the serotonin depletion study as an example. They decreased serotonin with pCPA, but that itself did NOT make the animals more depressed, it ONLY abolished the antidepressant effects of ketamine. Here are the values:

100% serotonin + placebo: ~130 secs immobility
100% serotonin + ketamine: ~90 secs immobility (-> antidepressant effect)
~30% serotonin + placebo: ~130 secs immobility
~30% serotonin + ketamine: ~120 secs immobility (no longer significant)

If I am not, I cannot see how this is proof that the suggested cascade is what causes the magical antidepressant effect of ketamine, especially because that effect does not end with ketamine and it's metabolites leaving the body. This cascade would e.g. not sufficiently explain how the effects of ketamine can persist so long and I don't understand why this wasn't taken into account at all, as I've stated earlier.

Ketamine's initial indirect 5-ht1a activation causes neurogenesis (depression is a neurodegenerative disorder), so even when ketamine is excreted, the newly created neurons are still gonna be there.

Thanks man! I'm not really into soccer, but tomorrow will be an important day for our city for sure. Losing would be a disaster. The players only have contract for the 1st league, same goes for the sponsors, so the club would be in deep shit. 2nd biggest city in Germany without a team in the first league, that's ridiculous.

It was a close one, but they made it

I assume you are living in Germany as well?

Yes