ACHs (ketamine, MXE etc) vs. DXM, ephenidine etc. - differing NMDA sub units?

[dopamimetic]

Might be that I'm an exception on this, but for me there are (at least) two groups of dissociatives. The 'good ones', the arylcyclohexylamines like ketamine, methoxetamine, 2'-oxo-PCE, even 3-MeO-PCP and to some extent memantine. Then that 'dirty ones', DXM/DXO, and diphenidine / methoxphenidine / ephenidine. I've read from others that the latter are different from the ACHs, more crazy etc. and for me they are heavily dysphoric, toxic feeling and a door to insanity while the ACHs are generally clean, bright and positive as long as the dose isn't too high.

I do have really limited chemical knowledge but it appears to me that DXM and the ephenidine etc. are structurally closely related and a bit different from the ACHs. Is this correct?

Could it be that these two groups act on different sub units of the NMDA receptor complex? Or is it about sigma agonism (but 3-MeO-PCP is a sigma agonist too, this might more contribute to its mania-inducing properties)?

 

[belligerent drunk]

For some reason I think DXM is subjectively different because it also acts on many other receptors, and you may not respond well to that.

As for the question about structures, no. DXM is significantly different from ephinidine and arylcyclohexylamines. DXM has a morphinan backbone, like classical opioids do. Ephinidine is actually quite similar to ACHs in that its basic nitrogen is bound to the same carbon with the aryl moiety, which is not the case for DXM and in fact the nitrogen is somewhat farther from the aromatic ring. I don't know what aspects of the structure are important for activity, but just plainly comparing the structures DXM is a lot more different from ACHs than ephinidine is and is different from ephinidine itself.

I find it quite interesting that some opioids and dissociatives are actually very similar in their structure.

 

[dopamimetic]

The pharmacological profile of DXM doesn't appear to be that dirty as it feels like, ketamine does act on at least as many different sites and it's much cleaner - but probably we just don't know why this is the case.

(besides the NMDA antagonism)

DXM:
- SERT (23 nM) and NET (240 nM) inhibitor
- Sigma 1 (150 nM) and 2 (11 uM) agonist
- nicotinic antagonist (uM range)
- mu, delta and kappa agonist (mu: 1,280 nM, the others even less)
- NADPH oxidase inhibitor

DXO:
- sigma 1 (118 nM) and 2 agonist
- SERT (484 nM) inhibitor
- nicotinic antagonist
- Glycine antagonist <--- maybe this one is relevant??
- L-type calcium channel blocker
- mu weak partial agonist / antagonist, kappa agonist

Ketamine:
- D2 agonist
- nicotinic negative allosteric modulator and weak muscarinic antagonist
- weak mu & kappa agonist (10-20x less than its NMDA potency) and very weak delta agonist
- SNDRI
- L-type calcium channel, sodium channel & HCN1 cation channel blocker
- nitric oxide synthase inhibitor <--- responsible for the bladder damage??
- sigma 1 & 2 agonist (uM range)

Memantine:
- nicotinic antagonist (equipotent to the NMDA site)
- D2 agonist (slightly above NMDA)
- 5-HT3 antagonist
- sigma1 agonist (2.6 uM)

DXM has a really unique, bad (side) effects profile. It is much more dysphoric for me too than the ACHs, it does readily induce tinnitus and scatter my mind in a way that is not really explainable by the data. Or it's about the glycine antagonism & sigma agonism - can't tell. Curiously part of the population appears to react this way to MXE too, there are reports about tinnitus etc. for it but it really seems to be dependent on the individual. This let me theorize about genetical variants of the NMDA complex and the different dissociatives binding to different sub sites in the one or other ...

Just thought that the molecular structures of ephenidine & dextro(meth)orphan do readily overlay and the ACH's are a bit farther away but I could have been wrong.

But yeah the similarity of opioids & dissociatives is remarkable indeed. When you look at lefetamine then ephenidine etc. should have opioid affinity too, but in the end it's not really sure how strong of an opioid lefetamine is ... there is downstream endorphin activity from NMDA antagonism and maybe this plays the main part?

There are opioid arylcyclohexylamines too, I heavily suspect the 3-HO-2'-OXO-PCE metabolite from methoxetamine to have opioid affinity too, 3-HO-PCE is an active opioid and it would explain part of the effects. Just that as long as the NMDA antagonism is stronger than the opioid agonism, one wouldn't develop opioid dependency / withdrawal and thus people think it isn't opioidergic.

 

[Solipsis]

I also rate NMDA antagonists / dissociatives, but I would not rate or categorize them bluntly into two groups, I think it is much more of a multivariable situation. I think it would be a bad idea to try and compare it to say GABAR with its subtypes. To some extent benzo's and nonbenzodiazepines (shit name lol! call them benzoids?) seem to be relatively okay to model and rate as for their binding profiles on or in between exactly which GABAR subtypes... then again even that can get very weird and easy to misunderstand for the half- or barely initiated. [I am - clearly? - not an actual pharmacologist], what with the extrasynaptic receptors and all?

For the purpose of this thread's question I think this is a good basis:
https://www.erowid.org/chemicals/dxm/faq/dxm_neuropharm.shtml >> NMDA receptor structure and function

I don't think DXM and the xphenidines should be considered alike, even if you have dirty / toxic / sketchy feelings about exactly that subset of dissos. DXM's multiple action makes things quite confusing, if DXO could be considered as isolated that would perhaps be another thing.

To begin with the xphenidines seem to be quite dizocilpine-like as hardcore uncompetitive PCP-site binding antagonists, but I don't think that their possible additional actions on monoamine transporters or some allosteric NDMAR site are known... so it would stop there. You'd have to case by case 'formulate your complaint' besides the dangerous amnesia + cognitive impairment, and it would have to be considered.

So I would combine the data with the above post, plus the action of ACH's on DAT which still seems poorly understood? And missed out on in that well-known binding data post..

Also it is worth considering that some secondary activity besides the NMDA antagonism may actually help make a dissociative at least somewhat functional and less impairing (DRI..) rather than dirty.. but then this is another potential source of worry, like the mania etc.

So my question, that I've raised before, is what makes a dissociative not functional in the sense that it doesn't immobilize (sure DRI could do that), but more recreationally safe in the sense that it DOES anaesthesize like the eutomer of ketamine?

When tiletamine / O-PCE are also considered, it becomes quite tricky because it makes the 'sweet spot' of a hole a complex thing since you don't want to cause immobile blackouts, not amnestic mobile (delirious) blackouts but - this may depend on the person or the situation - a working balance between these effects on cognition, awareness, memory and motor control.

 

[serotonin2A]

I think you need to consider the fact that a single pharmacological agent will have different dose-responses for its therapeutic effects and side-effects. Dextromethorphan is an antitussive at doses of 10-30 mg and it doesn't act as an NMDA receptor antagonist until you take dosages that are at least 10-fold higher. So in a way, DXM is only psychoactive at levels that could be considered to be an overdose (although obviously people are seeking those effects).

DXM has pretty high affinity for sigma-1, SERT and NET, and much lower affinity for NMDA receptors. Those figures don't tell the whole story because some DXM is converted to dextrorphan, which is a more potent NMDA receptor antagonist. But even taking dextrorphan formation into account, DXM ingestion is not going to block NMDA receptors without producing appreciable binding to sigma-1, SERT and NET.

Like DXM, dextrorphan also inhibits SERT (Ki 401 nM) and NET (Ki 340 nM). Dextrorphan is really a mixed NDMA-R antagonist and serotonin/norepinephrine uptake inhibitor. The action on NET induced by dextromethorphan and dextrorphan almost certainly has the potential to produce nasty side-effects at the doses people would use to block NMDA receptors.