Nagelfar
Bluelight Crew
Anybody have good information on Metaphit? Esp. a well drawn 2D molecular image? I'm wanting to add it to Wikipedia as a prime example of an RC. Apparently, it's covalent binding at NMDA sites, Sigma sites & DAT sites.
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N&PD Moderators: Skorpio
Metaphit
- Thread starter Nagelfar
- Start date
/navarone/
Bluelighter
Covalent receptor bonding? Woooh..this stuff sound dangerous. Imagine your sigma, DAT and NMDA receptors permanently bonded to a PCP like drug. I see many dying receptors in my chrystal ball...
Nagelfar
Bluelight Crew
Yes, it's pretty non-selective for a drug which causes an irreversible method of action. I made the article, could always add more however.
Source?
sekio
Bluelight Crew
Christ on a bicycle, this looks like a hilarious compound to dope someone's morning Cheerios with.
Nagelfar
Bluelight Crew
I can see the blank expression of wonderment on the unfortunate victims face after taking a heaping spoonful, imagining the severe ringing in their ears and their feeling of falling backward through space & time (Which won't stop for a day or two) yet not having words for those things. Yeah, be sure to take it on a non-work day.http://www.sciencedirect.com/science/article/pii/0014299987902834
wow I haven't ever thought that a PCP derivative could irreversibly bind to receptors. This article is interesting but also makes you see how animal testing doesn't tell us too much. The article states that "In whole animal studies, however, metaphit has been shown to have either antagonist or PCP-like actions depending upon the animal species used and the experimental variable evaluated."
Nagelfar
Bluelight Crew
I am not sure why it is worded like that, but I think that it might mean that it either has antagonist like effects like pcp or it blocks pcp from binding, therefore antagonizing its antagonist effects. Who knows though, apparently people weren't as well written in the late 80's.
Nagelfar
Bluelight Crew
So it attaches to the PCP binding site without PCP-like (antagonist) activity or with. That makes sense, because the drugs m-, & p-isococ have the same difference between them in their mechanism as ligands for DAT and its cocaine binding site. Metaphit might be liable to either conformation of binding.
specialspack
Bluelighter
But that paper specifically says:
What does one make of that?
Nagelfar
Bluelight Crew
There are so many alterations of a chemical in vivo following metabolic pathways due to different routes. My best other guess on the rest is that it bonds as a partial agonist covalently, and so displays some activity in the direction of those receptors being activated, all while antagonizing full agonists.
However I find that quoted part of the paper perplexing myself, I am not even sure what the author was trying to insinuate, esp. with "functional antagonism... unrelated to specific blockade"
specialspack
Bluelighter
I think it's pretty clear what they're suggesting - that metaphit does NOT bind irreversibly to the PCP site in vivo, and that it's antagonism of PCP effects is functional antagonism.
This paper - http://www.ncbi.nlm.nih.gov/pubmed/1826788 - suggests similar:
Nagelfar
Bluelight Crew
"Functional antagonism" meaning competitive NMDA antagonist (ulterior site) affinity?
But yet:
I am not erudite enough to know what is meant by verbage such as "induced passive avoidance deficit" (too many double negatives for me, and an unfamiliarity with the appropriated terminology). Though I glean from the second line that it hasn't *anything* to do with the NMDA receptor is that correct? So is metaphit then neither an NMDA antagonist nor an antagonist of PCP induced NMDA antagonism, or am I missing how it is then still one of those or thus related?
specialspack
Bluelighter
Nope, functional antagonism (or physiological antagonism) means that it reverses the effects of the drug through other mechanisms, not via the same receptor - the previous paper alludes to some "presynaptic mechanisms"
"Induced passive avoidance deficit" means that PCP induces a deficit in the passive avoidance task that the rats were given, compared to controls, so whatever receptor system mediates that effect, metaphit does not engage with.
It appears that in some animal species metaphit is a (functional) PCP antagonist (i.e. an antagonist of PCP's effects). Whether it accomplishes that antagonism by interacting with the NMDA receptor is not clear, but seems unlikely from these studies. The original paper that shows the in vitro results is here - http://www.ncbi.nlm.nih.gov/pubmed/2982662 - which interestingly found that only a certain percentage of the available PCP sites was acylated under any conditions, so it would appear that metaphit (in vitro, in the rat) irreversibly binds only to a certain sub-population of PCP sites, indicating that there are multiple types.
Nagelfar
Bluelight Crew
With how incredibly similar metaphit is structurally to PCP, this is most bizarre. Perhaps traditionally understood mechanisms for PCP and similar drug dissociative effects are not mediated as much through affinity to the NMDA receptors as thought, at least that would seem to be an indication to me.
Perhaps I've stumbled upon my intra-Ca+ channel dissociative molecule after all, without so realizing. (Alas, this particular instance, with metaphit, antagonizing what NMDA antagonism there is from elsewhere, is not quite what I had in mind, but a step in the right direction)
specialspack
Bluelighter
I really think you're barking up the wrong tree here... PCP et al are the intra Ca2+ blockers you're looking for. You're basing your speculation on a single unreferenced paragraph from wikipedia, which seems completely wrong!