MXE μ opioid binding affinity (or MXE on Methadone)

[serotonin2A]

MK-801 (aka dizocilpine) is actually fairly selective for d2h dopamine receptors (about 6x selectivity vs NMDA):
Dopamine receptor contribution to the action of PCP, LSD and ketamine psychotomimetics

I have NEVER seen an NMDA antagonist that has been proven to be selective.

Unfortunately the supposed data showing that MK-801 is a D2 agonist is utter BS. Only Seeman's lab has shown that, no one else. Until another lab duplicates his findings, you have to be very skeptical. It's not like it's difficult to do binding studies, so you have to wonder why only his lab can produce evidence for promiscuous binding to D2high. If Mk801 is a high affinity D2 agonist then it should be easy to confirm that in vivo, but there has never been any evidence that it directly activates D2.

 

[WSH]

Unfortunately the supposed data showing that MK-801 is a D2 agonist is utter BS. Only Seeman's lab has shown that, no one else. Until another lab duplicates his findings, you have to be very skeptical. It's not like it's difficult to do binding studies, so you have to wonder why only his lab can produce evidence for promiscuous binding to D2high. If Mk801 is a high affinity D2 agonist then it should be easy to confirm that in vivo, but there has never been any evidence that it directly activates D2.

Check out Seeman's studies, he even EXPLAINS the possible mistake that the other labs made (hypertonic buffer containing 150 mM NaCl).

Can you show me a study that found NO D2high activation that did NOT make this mistake?

Until you can do so, we should assume that it DOES activate D2high, because that's all the evidence we have right now.

 

[serotonin2A]

Check out Seeman's studies, he even EXPLAINS the possible mistake that the other labs made (hypertonic buffer containing 150 mM NaCl).

Can you show me a study that found NO D2high activation that did NOT make this mistake?

Until you can do so, we should assume that it DOES activate D2high, because that's all the evidence we have right now.

I'll try to find the reference you asked for. But you are kind of missing the point of how science is supposed to work. You never assume that something is true just because it was published. Plenty of papers get retracted and an even greater number are wrong. When faced with a new finding that contradicts previous data, you have to view it with a critical eye until the discrepancies are explained.

It is Seeman's responsibility to explain why there is absolutely no in vivo evidence to support his findings. Of course he proposed a potential explanation for why he found higher affinity than previous studies, because he wouldn't have been able to publish the paper if he didn't come up with some way to explain the discrepancy. But why is there no behavioral support for his findings? D2 agonists produce very specific behavioral signals that should be easily detectable. For example, apomorphine strongly disrupts prepulse inhibition (PPI) in rats and mice via D2. MK-801 disrupts PPI but the effect is not blocked by D2 antagonists. The same is true with locomotor activity. And there has been no evidence from D2 knockout mice that they are less sensitive to MK-801. If MK-801 is a direct D2 agonist then that should be detectable in rats with unilateral 6-OH-DA lesions, but again that doesn't seem to be the case.

There is also a bigger issue here. Seeman's data indicates that many drugs from different classes activate D2. Not just MK-801 and ketamine, but also LSD, salvinorin (if I remember correctly), and modafinil. Ask yourself this question: what do those drugs have in common? The answer is that they have very little in common from a pharmacological standpoint. Certainly they all have very different effect profiles in rodents and humans. There is nothing at all to indicate that they share a common mechanism of action. Salvinorin certainly does not act like a D2 agonist in vivo. So even if the D2 binding does occur with those drugs, one has to suspect that the interaction is not relevant to their psychoactive effects, otherwise there should be commonalities between the effects of all of those drugs. There is also the little problem of the fact that known D2 agonists such as apomorphine produce effects that are very different than MK-801 and the others. I don't see any evidence that the D2 story (if it is true) is relevant to the in vivo pharmacology of most of those compounds. Many drugs bind to H1 receptors, but that doesn't mean that it plays a primary role in their effects.

 

[serotonin2A]

Here is an established behavioral model that shows that MK-801 does not act as a D2 agonist in vivo: http://www.ncbi.nlm.nih.gov/pubmed/6146989

 

[DL-ark]

Thank you for your thorough reply.

It's true that I've completely forgotten to check the in vivo evidence.

That reminds me of 8-OH-DPAT. They have proven in vitro that it's a full agonist at inhibiting forskolin-stimulated cAMP production at postsynaptic 5-HT1A receptors in the hippocampus.
But then Montigny came along and proved that it's actually a rather weak partial agonist using in vivo electrophysiology.

So yeah, in vivo > in vitro.

I agree, MK-801 does NOT seem to produce its effects via D2 in vivo.

Has mu-opioid affinity been disproven in vivo for mxe?

 

[WSH]

Has mu-opioid affinity been disproven in vivo for mxe?

No, as far as I know there hasn't been any scientific MXE in vivo testing, neither for µ opioid nor for dopamine receptors, not even for NMDA antagonism.

 

[DL-ark]

No, as far as I know there hasn't been any scientific MXE in vivo testing, neither for µ opioid nor for dopamine receptors, not even for NMDA antagonism.

So is it then conceivable that MXE could have affinity for mu-opioid in vivo, it seems to roughly fit the SAR.

 

[WSH]

So is it then conceivable that MXE could have affinity for mu-opioid in vivo, it seems to roughly fit the SAR.

We can't say for sure until they do in vivo tests where they check for naloxone-reversible µ opioid like behavioral effects.

Everything else is speculation.

 

[sekio]

the ECMD found MXE did not bind to cloned human mu opioid recptors in vitro... I think that's damning enough evidence.

 

[endotropic]

If anyone is wondering where their posts went I split some discussion on in vivo vs. in vitro testing to its own thread.

 

[WSH]

the ECMD found MXE did not bind to cloned human mu opioid recptors in vitro... I think that's damning enough evidence.

But what about the metabolites of MXE, I don't think they have been tested yet.

The inventor of MXE also reported subjective opioid effects.

 

[dopamimetic]

For sure MXE does have subjective opioid effects in "naive" users. And they set in even before the dissociation, so it is likely to be the MXE itself causing them - but if it's direct agonism or some downstream or indirect effect, I have no clue. As someone wrote before, DXM has this opioid site too (despite its verry low binding values), at least as intense as with MXE but also with the tendency to go away irreversible after the first two trips or so.