Methoxetamine Pharmacology & Implications for Combinations

[Solipsis]

• At the moment our wiki article on MXE describes it's pharmacology as being an NMDA antagonist and dopamine reuptake inhibitor. Whether MXE is a DARI is discussed in ADD in this thread.
  
  SERT affinity was not so hard to find (source)
  
  DAT affinities in this study apparently were not usable, I am having a hard time finding other data so I guess MXE's DARI status remains speculative, though - as Sekio has already said in the other thread - extrapolating from other arylcyclohexylamines we would expect MXE to have appreciable affinity.
  
  So, should the wiki as well as the general perspective not be revised to consider MXE probably a DARI but certainly an SRI ?
  
• I have been updating the MXE combinations subthread in PD, and I welcome you to check it in the name of peer review.
  
  As you can see I am trying to make posts about complications resulting from MXE combinations more accessible and for the sake of HR I would like to discuss how we can interpret the available data and correlate it with anecdotal evidence. Obviously if there are warnings in the thread that have too weak a basis, I would like to remove them... and if we can make sense of some of these interactions in light of combined pharmacologies, we can try to keep some incidents from happening.
  I am also interested how findings translate to compounds such as 3-MeO-PCP, 4-MeO-PCP and 3-MeO-PCE and whether the things to avoid mixing with might be a little different compared to MXE.
  
  I guess to be more specific the bit about 'additional info on MXE with stimulants' is a prime topic to go on, since it seems so obvious that SRI action is relevant. But is it an illusion that dopamine reuptake inhibition combined with dopamine release is less dangerous? For example I have not heard explicit warnings about avoiding mixing amphetamines with MPH.

 

[sekio]

I would be more trusting of the ECMD report that suggests MXE has no or negligible DAT affinity, rather than extrapolation based on guessing.

 

[Solipsis]

You mean that ACMD report that leaves most discussion of it out altogether, other than mentioning that DAT was in the assay but not in the results?

I found a study that offers these same numbers, which may be the source of that report.

There was DAT affinity found for 3-MeO-PCP but not 4-MeO-PCP and methoxetamine.

While previous reports have implicated the dopamine transporter (DAT) and sigma receptors in the behavioural pharmacology of ketamine and PCP analogues [22]–[23], the present findings do not support these suggestions.

However the reason for that was explained thus:

Nishimura et al [22] found only weak effects of ketamine isomers on rat brain DAT (Ki = 50–390 µM) while Chaudieu et al [23] reported submicromolar potency for PCP and some related analogues. However, in the present study no appreciable affinity was observed for any compound at a concentration of <10 µM for hDAT in binding assays. The poor correlation with the results of Chaudieu et al [23] likely reflects the fact that the substrate can bind to different sites on the transporter than the radioligands used for displacement assays.

edit:

sorry I interpreted that upside-down, as I understand it they suggest that Chaudieu's study shows binding that is considered invalid?
Is there any way to know if the type of binding that was found would inhibit DA reuptake?

So, is this conclusive to say that MXE does not act as a DARI?

 

[sekio]

Is there any way to know if the type of binding that was found would inhibit DA reuptake?

Check the ligands used for the DAT displacement assay, I guess, or the best way would be to observe its effect in a biological system, like uptake of radiolabeled [3H]DA into CHO cells expressing DAT. Like an IC50 type thing.

So, is this conclusive to say that MXE does not act as a DARI?

I don't think we can tell. At the very least it does not behave like a classical DARI in binding to the same site we'd expect (cocaine site I'd guess). The possibility remains that it might bind to a different site, maybe a modulatory one, and effect dopamine efflux though.

 

[specialspack]

IIRC the data saying ketamine is a DARI comes from only one lab, Seeman at the University of Toronto.

A while ago, Dondante posted that a personal communication from Roth stated that he thought Seeman's results were rubbish, and no one else has been able to reproduce them. I think it was in the thread about the ACMD's report - possibly started by Transform?

EDIT - this thread here http://www.bluelight.ru/vb/threads/649843-Binding-data-for-popular-arylcyclohexamines

the poor correlation with the results of Chaudieu et al [23] likely reflects the fact that the substrate can bind to different sites on the transporter than the radioligands used for displacement assays.

I think what they're saying here is that the hot ligand used in the PDSP DAT assay - which is WIN 35428, according to their protocol book, is biding to a different site to PCP on DAT - as the Chaudieu paper is measuring the uptake of DA rather than binding of PCP to DAT (i.e a functional assay)

What I find completely bemusing is why the Roth and co in the PLOSone paper didn't run any functional assays at the same time as they were doing the binding assays?

 

[Solipsis]

...Alright, so the jury is still out? I am intrigued to find out what is going on with MXE's dopaminergic action (or rather on the transporter), but in the meanwhile could you (in)validate whether or not we can make educated guesses conductive to the aforementioned MXE combinations subthread @ PD ?