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Phenethylamines Structure of 5HT2a with 25CN-NBOH bound

Cool. It's really neat how psychedelics have unveiled so much about how the brain works historically (ie I believe LSD led to the understanding of there being receptor sites at all, or at least the existence of serotonin sites), and continue to do so. I wish I understood the implications of this better though. Can anyone explain this "toggle switch" they're talking about?

Is it like this: there's some kind of toggle switch within the receptor site that is either activated or not, and that agonists that bind to the site are activating the "switch" or displacing the tryptophan that's sitting in there, and causing the neuron to be excited, whereas a non-agonizing chemical that binds to the receptor site without activating that switch? Am I on the right track?
 
Watching the receptor under the influence of 5-meo-mipt.

The DNA is a fucking miracle developing and mutating in front of our eyes. We have millions and millions of these same structures packed in the brain...
 
Paper says” The 2-hydroxyphenyl moiety of 25CN-NBOH dives deep down into a previously undescribed pocket between TM3 and TM6, forming hydrophobic interactions with the indole ring of W336 (Figure 4B). For many years, this highly conserved W in class A GPCRs has been proposed as a “toggle-switch” to control GPCRs transitioning between “on” and “off” states during signaling transduction
perpetualdawn said:
Cool. It's really neat how psychedelics have unveiled so much about how the brain works historically (ie I believe LSD led to the understanding of there being receptor sites at all, or at least the existence of serotonin sites), and continue to do so. I wish I understood the implications of this better though. Can anyone explain this "toggle switch" they're talking about?

Is it like this: there's some kind of toggle switch within the receptor site that is either activated or not, and that agonists that bind to the site are activating the "switch" or displacing the tryptophan that's sitting in there, and causing the neuron to be excited, whereas a non-agonizing chemical that binds to the receptor site without activating that switch? Am I on the right track?
Click to expand...
I think they are saying this is one of the major ways that the 25N is turning the receptor on, by hitting the tryptophan that is down in a deep pocket, it is turning the receptor into a more “on” shape/state. Also some additional interactions with the 2-hyroxyphenyl.
Then they go on to describe a unique interaction of LSD with a serine that may be why it has such long binding kinetics.

Both LSD and 25N turn the receptor on, but by touching different parts of it (a sexy summary?)
 
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