Thank you for elucidating this paper. Greatly appreciated.
Do we currently have a clear understanding of why different signaling biases result in the various subjective effects of, for example, LSD versus LSA? Or do we only know that this is the case without further insight into how and why it happens?
We don't have a full picture yet no -- the neuron is a complex system embedded in a larger complex system (the cortex), so unravelling these things is extremely difficult. Computational systems biology models are likely to be useful in this regard I think.
This does not explain "long LSD" - like long COVID :)
As I rose up the ranks of the scientific and corporate world I started to wonder: where did all the acid heads go? Very few people who regularly dropped acid avoided dropping out.
No, it does keep that proton in the bound state, and a protonated amine is actually a major molecular recognition point for aminergic gpcrs. In the 5HT2B pdb structure that is discussed 5TVN this is also clear and the ammonium at N6 forms a strong interaction with Asp135.
I guess the question is where this proton is picked up. It's not the "same proton" as in the tartrate salt. The protonated form is unlikely to pass the BBB, so reprotonation occurs either inside the brain or within the binding site itself.
Nice write up! How feasible do you think it would be to concoct (protein engineering perhaps?) a LSD-esque DMT molecule that has the same binding properties? Perhaps including ergoline structure in it. Just curious if it even makes sense.
I'd suggesting avoiding using the ergoline structure since it's likely to be very difficult to match the signalling patterns with such a bulky group in the binding site. A bulky group on DMT that sits outside the binding site but acts as an anchor and increases the residence time is more feasible imho. But even then I think it's a tough ask.
Thank you for elucidating this paper. Greatly appreciated.
Do we currently have a clear understanding of why different signaling biases result in the various subjective effects of, for example, LSD versus LSA? Or do we only know that this is the case without further insight into how and why it happens?
We don't have a full picture yet no -- the neuron is a complex system embedded in a larger complex system (the cortex), so unravelling these things is extremely difficult. Computational systems biology models are likely to be useful in this regard I think.
These compounds remain such a fascinating mystery, thanks.
This does not explain "long LSD" - like long COVID :)
As I rose up the ranks of the scientific and corporate world I started to wonder: where did all the acid heads go? Very few people who regularly dropped acid avoided dropping out.
Since LSD is taken as a tartrate, i.e., the position-6 Nitrogen is protonated, is it then still the protonated molecule that winds up at receptors?
No, this proton is highly labile.
No, it does keep that proton in the bound state, and a protonated amine is actually a major molecular recognition point for aminergic gpcrs. In the 5HT2B pdb structure that is discussed 5TVN this is also clear and the ammonium at N6 forms a strong interaction with Asp135.
I guess the question is where this proton is picked up. It's not the "same proton" as in the tartrate salt. The protonated form is unlikely to pass the BBB, so reprotonation occurs either inside the brain or within the binding site itself.
You say LSD is just right, does this mean it is perfect or is there potential to improve it further?
Depends what you mean by improve? Always possible to create new analogues, but they'll likely be much less potent.
Improve potency, duration etc.
Nice write up! How feasible do you think it would be to concoct (protein engineering perhaps?) a LSD-esque DMT molecule that has the same binding properties? Perhaps including ergoline structure in it. Just curious if it even makes sense.
Thanks!
You mean a drug that has the effects of DMT but the duration of effects of LSD????
Exactly. I assume the ergoline structure is what increases its affinity to the receptor so maybe it is feasible?
I'd suggesting avoiding using the ergoline structure since it's likely to be very difficult to match the signalling patterns with such a bulky group in the binding site. A bulky group on DMT that sits outside the binding site but acts as an anchor and increases the residence time is more feasible imho. But even then I think it's a tough ask.
Thanks! That was insightful