What’s next?
The missing piece(s) of the puzzle are now the links between these biochemical events, and the parts of the brain that must be involved in changing consciousness. It will probably be a long time before this connection can be made. In the meantime, however, there are a number of scientifically valid approaches that will give useful information.
Recently, for example, we have “stumbled” upon a simple phenethylamine molecule that has affinity for the 5-HT2A receptor nearly 100-fold higher than any other compound discovered to date, including LSD itself! There is no particular reason to search for more potent compounds, but often such molecules prove to be quite useful as research tools. For example, when a molecule has very high affinity for a receptor, it is often possible to introduce radioactive atoms into the molecule that allow one to visualize sites where the molecule binds in the brain.
This has already been done with molecules such as DOB, DOI, and LSD. However, a molecule with even higher affinity can be used at lower concentrations and dosages to detect and visualize receptors. This new molecule, with exceedingly high affinity for the 5-HT2 class of receptors will no doubt be useful to label and visualize these receptors in the brain. Indeed, we have already begun discussions with a firm that supplies radioactive molecules to prepare radioactive forms of this molecule for evaluation. Literature reports now also suggest that a tentative 3 dimensional structure for the family of Gprotein coupled receptors may not be far off. This is the receptor family to which nearly all of the serotonin receptors belong. Perhaps within the next year or two a good structure may become available. With that event, we would begin computer modeling studies to dock our molecules into this receptor structure in attempts to gain an appreciation of which structural features of the molecule are necessary for binding and activation of the receptor. If this can be accomplished, we should also be able to design new molecules to test hypotheses about which molecular features are necessary for receptor binding.
That would be a very exciting development because it would be the first time that it might become possible to design a molecule, de novo, to fit a particular receptor. Clearly, if we can retain our research funding, the most exciting developments in the medicinal chemistry of psychedelic agents are yet to come.