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Binding data for popular arylcyclohexamines.

Binding affinities as Ki (not pKi)

Ketamine, NMDA: 661 nM +/- 98

PCP, NMDA: 59 +/- 9 nM (~10x ketamine)
PCP, SERT: 2239 +/- 243 nM
PCP, Sigma2: 151 +/- 28 nM

MXE, NMDA: 257 +/- 33 nM (~2.5x stronger than ketamine)
MXE, SERT: 479 +/- 52 nM

4-MeO-PCP
NMDA: 407 +/- 53 nM (~1.6x ketamine)
SERT: 851 +/- 93 nM
NET: 794 +/- 13 nM
Sigma1: 316 +/- 65 nM
Sigma2: 12 +/- 2 nM

3-MeO-PCP
NMDA: 20 +/- 3 nM (~30x ketamine)
SERT: 200 +/- 41 nM
Sigma1: 40 +/- 8 nM

No binding at any opioid receptors either~! (or any other receptors that were tested) So put to rest this myth that MXE/3-MeO-PCP have "opioid effects". Guess most of them are piss poor DAT substrates too.
 
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at least these NMDA binding affinities seem to completely confirm/very directly corellate with previously reported dosage levels
 
Finally some evidence to back up my claim that MXE most likely had SERT affinity and this was why it was playing bad in some combinations with serotonergics.

Guess my theory about MXE being a mild mu-opioid agonist was utter bollocks though. :p

Though, I wonder if maybe the SERT affinity is actually responsible for the opioid like warmth I experienced after all. I remember comparing IAP to opioids because of the similar warmth it gave me, when it's pretty much only a serotonin releaser.
 
so is the lack of activity in other then the nmda sites with ketamine the reason it is so easy to hole on it ?
 
3- and 4-MeO-PCP are lookin' pretty neat considering that sigma receptor agonists and NMDA antagonists produce a synergistic antidepressant effect.

The aim of the present study was to examine the effect of combined administration of sigma1 or sigma2 receptor agonists, SA4503 or siramesine, respectively, and AMA or memantine (MEM) (uncompetitive NMDA receptor antagonist). SA4503 or siramesine given jointly with MEM (as well as with AMA) decreased the immobility time in rats. The effect of SA4503 and AMA co-administration was antagonized by progesterone, a sigma1 receptor antagonistic neurosteroid. Combined treatment with siramesine and AMA was modified by neither progesterone nor BD1047 (a novel sigma antagonist with preferential affinity for sigma1 sites); but it was counteracted by sulpiride and prazosin (a dopamine D2- and an alpha1-adrenergic receptor antagonist, respectively). The "antidepressant-like" effect induced by siramesine and MEM was not antagonized by progesterone, but was attenuated by BD1047, sulpiride and prazosin. The obtained results give support to the hypothesis that sigma (particularly sigma1) receptors may be one of the possible mechanisms by which drugs induce antidepressant-like activity in the forced swim test, and that this effect may be enhanced by NMDA receptor antagonists.
Click to expand...
 
Gaius said:
3- and 4-MeO-PCP are lookin' pretty neat considering that sigma receptor agonists and NMDA antagonists produce a synergistic antidepressant effect.
Click to expand...

Do we know whether 3/4-MeO-PCP are agonists or antagonists at the sigma receptors? Also there is a big difference between how uncompetitive antagonists like memantine work and noncompetitive antagonists like the arylcyclohexylamines (uncompetitive antagonists paradoxically produce more blockade at higher concentrations of Glutamate, whereas noncompetitive simply shift glutamate's concentration/effect curve rightward).
 
I believe that PCP has been found to be a sigma agonist, no reason to believe that the methoxy-PCPs would not be agonistic too.
 
sekio said:
I believe that PCP has been found to be a sigma agonist, no reason to believe that the methoxy-PCPs would not be agonistic too.
Click to expand...
but according to the data given in this report, neither ketamine nor methoxetamine have significant sigma activity. surprising...? :?

well, at least for me it is, somehow. wasn't sigma receptor activation considered the main pathway for dissociation for some time, until it was discovered that the NMDA antagonism plays the dominant role?

anyhow, what I am trying to say: these arylcyclohexylamines seem to me to have a damn complex pharmacology. my gut feeling says: expect the unexpected! ;)
 
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I believe a lot of these ACH drugs are very promiscuous, that is - K will still have affinity for sigma1/2, just not a large amount (less than 50% occupancy @ typical dose levels) And of course, a K-hole dose is much higher than a line dose, so maybe there's different pharmacology?

Maybe the same happens to the DAT? I dunno,. Talking out my ass.

The sigma receptor to me has always been a bit of an afterthought as a drug target. Straight sigma receptor agonists don't seem to do much but induce seizures and things like that I thought?
 
This study isn't the be all, end all. I think the ACH's effect on dopamine is more so from downstream action via NMDA antagonism, PCP2, sigma, etc. . . PCP and friends have been shown to party with dopamine in a not insignificant fashion in various Ways in various studies, and also not, or at least not significantly, in others. Sure seems like it has something, a lot of something, going on in them there regions! And let's not forget BTCP heheh! Complex pharmacology here. . .
http://www.nature.com/mp/journal/v7/n8/full/4001093a.html
http://onlinelibrary.wiley.com/doi/...ionid=4DBADBE49580286748F97C2C155FF565.d02t04
http://www.ncbi.nlm.nih.gov/pubmed/2557536
http://www.ncbi.nlm.nih.gov/pubmed/2544905
 
If MXE has no affect on dopamine than perhaps we need to re-evaluate which pathways are responsible for reward/reinforcement.

I think it's more likely that MXE and Ketamine both have significant action downstream.

In terms of pure satisfaction and hedonistic value I would always take a line of K or MXE over cocaine. I highly doubt it might be true that in fact I do not enjoy a good dopamine hit.
 
these dissociatives perhaps increase the response to dopamine-releasing-stimuli?

i.e. gambling while on MXE might cause a higher spike of dopamine, but sit around doing nothing on MXE and your dopamine levels will remain normal?
 
bluedolphin said:
If MXE has no affect on dopamine than perhaps we need to re-evaluate which pathways are responsible for reward/reinforcement.

I think it's more likely that MXE and Ketamine both have significant action downstream.

In terms of pure satisfaction and hedonistic value I would always take a line of K or MXE over cocaine. I highly doubt it might be true that in fact I do not enjoy a good dopamine hit.
Click to expand...

Dopamine is not in itself a "reward chemical." A certain study comes to mind in which researchers fried the basal dopamine pathways in mice so that they didn't seek out food, but then manually fed them and recorded their facial expressions (which supposedly indicate reward). There was no difference in facial expression between the dopamine-less and normal mice.
If it made sense to reduce complex neural pathways to the specific chemicals that jump across the synapse, then dopamine would be a salience/motivation chemical. I don't know much about glutamate's role in the nucleus accumbens/VTA but I'm willing to bet it's intimately involved, being many many times more prevalent than the monoamines.
 
Interesting that Roth is rubbishing Seeman's lab's reported claims of ketamine having a high affinity for D2 (quoted at 0.5 microM in the paper atrollappears references). He's right in that I'm unaware of any other studies that would back this up though.

In reference to kappa receptors, this paper - http://www.ncbi.nlm.nih.gov/pubmed/20358363 - reports Ki value of 25 microM for ketamine at human KOR. And Roth is one of the co-authors on that.

I'm also unclear from the ACMD's report if the actually commissioned the NIMH PDSP to do the screening of if it had already been done. Not that it really matters, just curious.
 
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sekio said:
Binding affinities as Ki (not pKi)

Ketamine, NMDA: 661 nM +/- 98

PCP, NMDA: 59 +/- 9 nM (~10x ketamine)
PCP, SERT: 2239 +/- 243 nM
PCP, Sigma2: 151 +/- 28 nM

MXE, NMDA: 257 +/- 33 nM (~2.5x stronger than ketamine)
MXE, SERT: 479 +/- 52 nM

4-MeO-PCP
NMDA: 407 +/- 53 nM (~1.6x ketamine)
SERT: 851 +/- 93 nM
NET: 794 +/- 13 nM
Sigma1: 316 +/- 65 nM
Sigma2: 12 +/- 2 nM

3-MeO-PCP
NMDA: 20 +/- 3 nM (~30x ketamine)
SERT: 200 +/- 41 nM
Sigma1: 40 +/- 8 nM

No binding at any opioid receptors either~! (or any other receptors that were tested) So put to rest this myth that MXE/3-MeO-PCP have "opioid effects". Guess most of them are piss poor DAT substrates too.
Click to expand...

Sekio where's this data from - it looks almost but not quite identical to the data quoted in the ACMD document...?
 
I was under the impression that MXE was not a dopamine agonist, but a dopamine reuptake inhibitor, which was how it affected the dopamine system.

Does this research negate that possibility?

It's effects on the serotonin system definitely gives me evidence as to the cause of the effects felt when I combined it with LSD. That was more powerful than I had anticipated, and have yet to repeat the combination due to it.

Edit: Could the Sigma-2 activation of PCP perhaps be the cause of it's psychosis risk? Several other drugs which have psychosis risks also activate Sigma (Ampehtamines/Cocaine and a few other psychedelics) and the anti-psychotics Haloperidol antagonises Sigma.
 
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specialspack said:
I'm also unclear from the ACMD's report if the actually commissioned the NIMH PDSP to do the screening of if it had already been done. Not that it really matters, just curious.
Click to expand...

Harry Sumnall of the ACMD: "if I recall correctly Brian Roth analysed it at ACMD request as part of the NIDA screening programme"
 
awildtrollappears said:
Not true: http://www.ncbi.nlm.nih.gov/pubmed/17666455
Click to expand...

I stand corrected. I was thinking of reuptake "blocking" in overly monolithic terms, as direct interference with the transporter, but it looks like there's a wide number of mechanisms that can affect transporter efficacy. I found the wording in the abstract a bit confusing, so here's where they lay out the mechanism in the text:

"Whereas synthetic antidepressants are competitive inhibitors of the respective transporter proteins, hyperforin reduces monoamine uptake by elevating the intracellular sodium concentration ([Na+]i) and thereby decreasing the sodium gradient as the driving force of these neurotransmitter transporters."

ebola
 
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