You wrote, "At higher, more challenging doses, ketamine can also gate access to entirely new reality channels populated by intelligent entities." Have you looked at the 2022 Nobel Prize in Physics which was given for showing instances of "spooky" as Einstein called them, or paranormal events at a subatomic level? The Nobel Prize winners go on to make a distinction between places which are local and places which are nonlocal. Do these intelligent entities reside in a place which is nonlocal? Or, are these intelligent entities simply fabrications of one's own imagination? What scientific criteria would you suggest to investigate and find answers to these questions?
The 5HT2A and NMDA receptors are completely different structurally with entirely different pharmacophores, so it's not going to be easy to find a molecule that's both an agonist at 5HT2A and an antagonist at NMDA. Not impossible though, but I'm not aware of any. However, ketamine *is* also an agonist at the kappa opioid receptor, which is surprising and fascinating, since it suggests it might contribute to the psychedelic effects (salvinorin is a kappa agonist and its psychedelic effects depend on this interaction). More on this in a later post.
Regarding sigma receptors, there's no evidence they have a major role in the acute effects of the psychedelics. Their effect is most likely to be on plasticity and other longer term neural changes.
I strongly agree that the structural landscape provides an immense challenge to find an overlap, but as you suggest, it is not impossible. Perhaps the interesting overlap might fall into the kappa opioid receptor too. Are there any demonstrated 5HT2A agonists/kappa (partial) agonist? I never thought to look at that overlap.
The reason I even entertain this idea is how some psychonauts will purposefully mix these classes of substances to experience a desired reality switch. If we are genuinely curious about the next steps in this technology, finding examples of these overlaps could deem useful. Perhaps it will require alternative engineering, such as oligonucleotide aptamers, to contort one of the receptors into a more desirable structure to enable a novel binding pocket. The groundwork for RNA Nanotechnology to enable CNS-active nucleic acid drugs is there, but unfortunately, there is no good examples of GPCR aptamers relevant to human psychoactive drug receptors, to the best of my knowledge (closest thing was an AMPA receptor aptamer 10.1016/j.neuropharm.2021.108761 something to think about)
You wrote, "At higher, more challenging doses, ketamine can also gate access to entirely new reality channels populated by intelligent entities." Have you looked at the 2022 Nobel Prize in Physics which was given for showing instances of "spooky" as Einstein called them, or paranormal events at a subatomic level? The Nobel Prize winners go on to make a distinction between places which are local and places which are nonlocal. Do these intelligent entities reside in a place which is nonlocal? Or, are these intelligent entities simply fabrications of one's own imagination? What scientific criteria would you suggest to investigate and find answers to these questions?
No common examples of substances which exhibit 5HT2a agonism and NMDA antagonism… And where does the SIGMA receptors come into play?
The 5HT2A and NMDA receptors are completely different structurally with entirely different pharmacophores, so it's not going to be easy to find a molecule that's both an agonist at 5HT2A and an antagonist at NMDA. Not impossible though, but I'm not aware of any. However, ketamine *is* also an agonist at the kappa opioid receptor, which is surprising and fascinating, since it suggests it might contribute to the psychedelic effects (salvinorin is a kappa agonist and its psychedelic effects depend on this interaction). More on this in a later post.
Regarding sigma receptors, there's no evidence they have a major role in the acute effects of the psychedelics. Their effect is most likely to be on plasticity and other longer term neural changes.
I strongly agree that the structural landscape provides an immense challenge to find an overlap, but as you suggest, it is not impossible. Perhaps the interesting overlap might fall into the kappa opioid receptor too. Are there any demonstrated 5HT2A agonists/kappa (partial) agonist? I never thought to look at that overlap.
The reason I even entertain this idea is how some psychonauts will purposefully mix these classes of substances to experience a desired reality switch. If we are genuinely curious about the next steps in this technology, finding examples of these overlaps could deem useful. Perhaps it will require alternative engineering, such as oligonucleotide aptamers, to contort one of the receptors into a more desirable structure to enable a novel binding pocket. The groundwork for RNA Nanotechnology to enable CNS-active nucleic acid drugs is there, but unfortunately, there is no good examples of GPCR aptamers relevant to human psychoactive drug receptors, to the best of my knowledge (closest thing was an AMPA receptor aptamer 10.1016/j.neuropharm.2021.108761 something to think about)