pharmakos
Bluelighter
UR-144 feels like low mids... stony body buzz, sedating, gives the munchies hardcore, but nothing too "WHOA" mentally (though there is a bit of a head high). UR-144 is "creeper" as well
N&PD Moderators: Skorpio | someguyontheinternet
If something is a suicide substrate (like a covalently binding agonist) then eventually receptor internalization will occur (and the receptor is replaced eventually). However until internalization occurs signal transduction can usually still take place so the effect of an irreversible agonist is not that of an antagonist, effectively, because the receptor population is not immediately destroyed.
So this is during a coffee break before a lab so bear with:
Well most of the problem comes from the fact that using traditional SAR, as things become more selective for DAT vs NET it also starts to bind to other things, for example meth vs regular amp. DAT just loves those oily mofo's.
But what I was getting at is the PKC mediated releasing action really isn't that different for NE vs DA, so using the traditional amphetamine MOA isn't ever really going to give you a greater DA/NE ratio. However, for reuptake inhibitors or things that bind to things like 5ht3 or NAChR there is a strong possibility for making a "selective" indirect DA agonist.
I'll post more when I have more time.
Aha! Another piece of the puzzle that I didn't understand. So amphetamine-like efflux is achieved by the exogenous ligand inducing PKC to phosphorylate the transporter (by binding to PKC, changing its conformational form?). Okay, so if this mechanism is fundamentally similar whether we're talking about DAT or NET, why do releasers have any selectivity at all? Are there different isoforms of PKC present proximate to different transporters?
ebola
You guys interested in making a thread out of the NE/DA efflux ratios topic?
Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.
Er...it's actually releasers where the topic becomes interesting; we've already developed highly selective DARIs.
ebola
There's no actual "need" for them in the market, but its interesting as sin to discuss and who knows where the conversation will turn. Someone post the OP and I'll get around to the new thread by Sunday.If you have selective DARIs then what is the need for the releasers?
Also, its PKC-beta that's responsible in neurons, not sure if its expressed significantly in GI cells.
If you have selective DARIs then what is the need for the releasers?