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MXE and opiate receptor affinity

laCster

Bluelighter
Joined
Nov 16, 2010
Messages
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my fellow bluelighters, do you believe MXE has--if any--affinity to bind to any of the opiate receptors??
at low doses (20-30 mgs), my pupils constrict to the size of pin-points. in addition, i get an opiate-like euphoria similar to 30mgs of oxycodone.

thanks,
-lacster
 
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It bears much resemblance to tramadol and I pondered about it as well but later concluded it doesn't to a significant degree, it doesn't follow the morphine rule even a tiny bit. However many opioids don't truly follow the morphine rule though they all share one detail which is necessary for activity and that is a fully alkylated amine.

I've had lot of experience...even to much experience with methoxetamine and aside from a highly psychedelic and serenic experience at very high doses, I cant recall feeling a noticeable opioid effect even when IVing.
Methoxetamine is also a dopamine reuptake inhibitor which usually dilates the pupils so it's funny you get such elevated constriction at low doses.
The time I was hospitalized for methoxetamine "overdose" doctors reported limited respone of the iris and a slight respiratory depression before I woke up but that was not really unexpected since IVd about 150+mgs.

Regarding ketamine I found this though on wiki:

Ketamine is a noncompetitive NMDA receptor antagonist. This receptor opens in response to binding of the neurotransmitter glutamate, and blockade of this receptors is believed to mediate the analgesic (reduction of pain) effects of ketamine at low doses. Evidence for this is reinforced by the fact that naloxone, an opioid antagonist, does not reverse the analgesia. Studies also seem to indicate that ketamine is "use dependent" meaning it only initiates its blocking action once a glutamate binds to the NMDA receptor.

At high, fully anesthetic level concentrations, ketamine has also been found to bind to opioid mu2 receptors in cultured human neuroblastoma cells without being an agonist on them and sigma receptors. It has also been shown to act as a weak D2 receptor partial agonist in rat brain cell homogenates, as well as a dopamine reuptake inhibitor.
 
This is kinda related. 2 weeks ago I would get a similar high from 30mg of morphine as to the high I have today from 70mg, here's the tricky part; I have not used morphine or any other opiate in that time. I did however use MXE 10 out of 14 days. Could it be more potent activity than thought but hidden by the strong dissociation effects?

On topic, on all doses of MXE my pupils are constricted to normal. After dosing MXE near daily my pupils have been dinner plates when not on MXE, even under high amounts of artificial light. I am guessing this is from the DRI action?
 
Note that many opioids also act on sigma receptors. This even led scientists to put these receptors into the group of opioid receptors. E.g. morphine is a sigma agonist but its affinity there is very low so this property doesn't play much of a role in the general action. Also, many opioids are also NMDA channel blockers. NMDA channel and sigma receptors happen to be in the same regions of human brain thus many NMDA blockers also act on sigma receptors. So it wouldn't be much of a surprise if there was found some evidence that opioid receptors, sigma receptors, and NMDA channel are all so close that substances acting strong on one have some impact on others, be it strong or light. But that's just theorizing. A good example of an opioid that acts on mu, kappa, and delta opioid receptors, and also activates sigma receptors and blocks NMDA channel is levorphanol, besides it's a weak SNRI; thanks to all these properties levorphanol is effective against a wider range of types of pains than morphine.

Again, about arylcyclohexylamines, they don't follow the morphine rule but there are some derivatives of PCP that are more of opioid agonists than NMDA blockers. The best example known to me is 4-phenyl-4-(piperidin-1-yl)cyclohexanone - it has no PCP-like activity but it's an active morphine-like analgesic. Also, PCP also was found to have some affinity to opioid receptors. 3-hydroxy-PCP is 8 times as strong as PCP as a dissociative but it's over 400 times as strong as PCP as an opioid agonist!

Analyzing methoxetamine's structure, you see that the piperidine ring is torn apart and there's a secondary amine with the best group on the nitrogen for dissociative effects, i.e. ethyl. 2-carbonyl group is known to boost affinity for opioid receptors in a lot of PCP derivatives, the simplest being 2-oxo-PCP, but also this group shortens the action and eases the metabolism. There's nothing on ortho position and it's known that groups that withdraw electrons decrease psychotropic action, in methoxetamine there's hydrogen there. And now meta position, there's a -OMe group. It's not as effective as simple -OH, it's bigger and one additive carbon atom has an impact on the potency in general but it's still a good substitute for -OH (well, I still wonder why a drug with -OMe got into online vendors' list of RCs instead of the same drug but with -OH, maybe it's for dosing reasons - theoretically 3-OH-methoxetamine could be 8 times as strong). Methoxetamine unavoidably has a structure that fits the rules for arylcyclohexylamines to be opioid agonists.
 
If it is an opioid agonist it definitely has something unique to it versus traditional opioid agonists. I don't get itching from MXE, whereas vicodin and oxycodone made me itch a bunch. I do get mild pain relief, but nothing like the total body numbness and general loss of muscle coordination that vic/oxy would give.

It is possible the interaction with NMDA receptors causes a downstream effect on opiate signaling, possibly to make endogenous pain relief signals work for longer periods of time. There is emerging research on ketamine, NMDA receptors and their relationship to pain signaling (see below, there's other recent papers out too). Certainly MXE cannot be that far behind given its explosion in popularity. It could even be a weak opioid agonist, but have a second mechanism mediated by NMDA that causes a more profound total effect at reducing pain or producing opiate-like effects.

J Neurochem. 2011 Oct;119(2):294-302. doi: 10.1111/j.1471-4159.2011.07361.x. Epub 2011 Sep 20.
Potentiation of μ-opioid receptor-mediated signaling by ketamine.
Gupta A, Devi LA, Gomes I.
Source

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA.
Abstract

J. Neurochem. (2011) 119, 294-302. ABSTRACT: Ketamine, a clinically relevant drug, has been shown to enhance opioid-induced analgesia and prevent hyperalgesia. However, the molecular mechanisms involved are not clearly understood. As previous studies found that activation of opioid receptors leads to the phosphorylation of mitogen-activated protein kinases, we investigated whether ketamine could modulate μ-opioid receptor (μOR)-mediated ERK1/2 phosphorylation. We find that acute treatment with ketamine enhances (∼2- to 3-fold) the levels of opioid-induced ERK1/2 phosphorylation in recombinant as well as cells endogenously expressing μOR. Interestingly, we find that in the absence of ketamine ERK1/2 signaling is desensitized 10 min after opioid exposure whereas in its presence significant levels (∼3-fold over basal) are detected. In addition, ketamine increases the rate of resensitization of opioid-mediated ERK1/2 signaling (15 min in its presence vs. 30 min in its absence). These results suggest that ketamine increases the effectiveness of opiate-induced signaling by affecting multiple mechanisms. In addition, these effects are observed in heterologous cells expressing μOR suggesting a non-NMDA receptor-mediated action of ketamine. Together this could, in part, account for the observed effects of ketamine on the enhancement of the analgesic effects of opiates as well as in the duration of opiate-induced analgesia.
 
I have a strong feeling that, like ketamine, MXE's purported "opioid" effects are only present at abnormally high doses and do not contribute to the recreational "flavour" of the drug.

I think this is kind of like the clonazepam<->serotonin association, simply because one journal paper mentions the two together, or shows some interesting secondary linkage, does not mean they are intimately related. Sure, 3-OH-PCP and others have affinity for MOR but 3-meo-pcp is not MXE.

Oh, that and mentioning that a drug has opioid effects will drive the downer-loving masses wild because opioid activity obviously equates to a heroin substitute. Free marketing!

I'd like to see some molecular dynamics simulations of ketamine/MOR and MXE/MOR binding though. Maybe that's a rainy day project.
 
thank you for shinning more light on this topic, sekio; your insight is always appreciated. do you believe sigma-receptor affinity contributes to MXE's recreational effects?
 
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The sigma receptor is very strange, I think it's definitely got something to do with dissociative.euphoric effetcs given the huge number of substrates that intract with it.
 
It could even be a weak opioid agonist, but have a second mechanism mediated by NMDA that causes a more profound total effect at reducing pain or producing opiate-like effects.

sekio said:
I have a strong feeling that, like ketamine, MXE's purported "opioid" effects are only present at abnormally high doses and do not contribute to the recreational "flavour" of the drug.

laCster said:
thank you for shinning more light on this topic, sekio; your insight is always appreciated. do you believe sigma-receptor affinity contributes to MXE's recreational effects?

I guess my post just wasn't worth reading was it? Oh no something that was actually backed up with an actual piece of science and not purely here say couldn't possibly be read or appreciated.

I bet the sekio sigma response will blow some minds as well.

Just in case it does, I'll make another comment for people to steal or blow over that isn't just here say.

There is yet to be much definite pharmacological characterization of sigma receptors in humans, so it is hard to say precisely what they do. Sigma 2 receptors are being investigated for cancer treatment. Sigma 1 seem to have gained more steam around the area of cognition, perhaps related to neurite outgrowth and has been well investigated for being involved with the effects of cocaine. Another paper I found says a sigma 1 agonist attenuates the stimulant effects of methamphetamine.

Some other interesting new research on sigma 1 can be found related to NMDA receptors:

Neuroscience. 2011 Mar 17;177:12-22. Epub 2011 Jan 4.
Activation of the sigma receptor 1 suppresses NMDA responses in rat retinal ganglion cells.
Zhang XJ, Liu LL, Jiang SX, Zhong YM, Yang XL.
Source

Institute of Neurobiology, State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China.
Abstract

The sigma receptor 1 (σR1) has been shown to modulate the activity of several voltage- and ligand-gated channels. Using patch-clamp techniques in rat retinal slice preparations, we demonstrated that activation of σR1 by SKF10047 (SKF) or PRE-084 suppressed N-methyl-D-aspartate (NMDA) receptor-mediated current responses from both ON and OFF type ganglion cells (GCs), dose-dependently, and the effect could be blocked by the σR1 antagonist BD1047 or the σR antagonist haloperidol. The suppression by SKF of NMDA currents was abolished with pre-incubation of the G protein inhibitor GDP-β-S or the Gi/o activator mastoparan. We further explored the intracellular signaling pathway responsible for the SKF-induced suppression of NMDA responses. Application of either cAMP/the PKA inhibitor Rp-cAMP or cGMP/the PKG inhibitor KT5823 did not change the SKF-induced effect, suggesting the involvement of neither cAMP/PKA nor cGMP/PKG pathway. In contrast, suppression of NMDA responses by SKF was abolished by internal infusion of the phosphatidylinostiol-specific phospholipase C (PLC) inhibitor U73122, but not by the phosphatidylcholine-PLC inhibitor D609. SKF-induced suppression of NMDA responses was dependent on intracellular Ca2+ concentration ([Ca2+]i), as evidenced by the fact that the effect was abolished when [Ca2+]i was buffered with 10 mM BAPTA. The SKF effect was blocked by xestospongin-C/heparin, IP3 receptor antagonists, but unchanged by ryanodine/caffeine, ryanodine receptor modulators. Furthermore, application of protein kinase C inhibitors Bis IV and Gö6976 eliminated the SKF effect. These results suggest that the suppression of NMDA responses of rat retinal GCs caused by the activation of σR1 may be mediated by a distinct [Ca2+]i-dependent PLC-PKC pathway. This effect of SKF could help ameliorate malfunction of GCs caused by excessive stimulation of NMDA receptors under pathological conditions.

Here you will see this group characterized sigma 1 to suppress NMDA receptor activity. It is not unfeasible to think a molecule like MXE, which is very potent and effective at what it does, could have multiple mechanisms at shutting down NMDA activity. It could be an equally, or nearly equally, potent NMDA antagonist and sigma 1 agonist, resulting in a broader and more effective mechanism for NMDA activity suppression than either alone is capable of.

There is some work characterizing ketamine and sigma 1 activity as well, which would further support that MXE has some activity there. The paper below is the only recent publication to appear in this area though.

Eur Neuropsychopharmacol. 2011 Sep 10. [Epub ahead of print]
Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo.
Robson MJ, Elliott M, Seminerio MJ, Matsumoto RR.
Abstract

Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to σ receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ(1) and σ(2) receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ(1) and σ(2) receptors with μM affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.

Recognize they use ketamine to displace the sigma antagonists, to show it is a specific sigma 1 or 2 agonist with "uM affinity." Hence the true potency at a sigma 1 agonism, without the presence of an antagonist, is probably in the range of 10-100 nM.

Also recognize sigma receptors are located inside the cell, so ketamine or MXE would also have to pass into the cell first to show this activity. This complicates things quite a bit, and would suggest effects at sigma receptors are probably secondary to primary action at cell surface targets.

I am not sure how the study I posted above gets ketamine to show good activity at sigma receptors then. Either it passes through the neurite passively, or sigma receptors are not always located inside the cell (instead sometimes at the membrane) as many other publications have indicated.
 
:)

I would expect a lot of these things are currently being studied by at least one or two academic labs in Europe. In a year or two hopefully sooner we should see their results published to confirm or expand some of these hypotheses.

I doubt any US or other groups are really looking into MXE though because the chemical originated in Europe and hasn't really gotten much publicity in the US or Asia, or elsewhere from what I can tell.

Of course if I were running a lab in the US, studying this field, I would be all over it already but I am still a bit young to be making these types of things happen. And as some of us already (unfortunately) know, 98% of academia is 2 years behind what the recreational drug scene is doing at any given moment.
 
Oh, that and mentioning that a drug has opioid effects will drive the downer-loving masses wild because opioid activity obviously equates to a heroin substitute. Free marketing!

it wasn't a ploy to market drugs to naive people... but then you probably are aware of the actual reason why the supposed increased opioid activity/3-MeO group was actually chosen for this drug, no?
 
the inventor of Methoxetamine was searching for a drug that would help treat his phantom limb pain, and thought that the added opioid activity of the 3-meo group would be beneficial there.
 
i can see how and why. i feel completely numb and disoriented from my body on MXE
 
I conclude based on my own research that there is zero or otherwise totally insignificant mu-opioid agonism taking place.

I say this based on the fact that I have, several times, gone through amounts of about 20g over the course of several weeks, then quit abruptly, with no withdrawl symptoms other than the feeling of "well, shit, party's over, back to normal now".

If I was to take oxycontin for even 4-5 days in a row I'd feel pretty grumpy and like I was about to catch cold if I stopped. This is not the case at all with methoxetamine. Withdrawl is purely psychological, and that will depend on the person and their particular circumstances.
 
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