The beta carboline scaffold is probably going to yield some psychedelic compounds, but IDK if anyone will ever taste the compounds in question or if they will be interesting enough to be distributed once somebody does. There’s a lot of tasting and screening to do if somebody was interested in exploring a whole new area.
Psychadelic lovers know that 5HT2A and 5HT2C are the key thing that we want to see stimulated, even if 2A is the main target and 2B is rumored to be involved in tactile distortion. For example, at a concentration of ~3nM, LSD occupies half of 5HT2A receptors, at a concentration of ~10nM, LSD occupies half of 5HT2C receptors, and at a concentration of ~30nM LSD occupies half of 5HT2B receptors. Plasma concentrations of LSD seem hard to come by but I've seen a range between 1 and 10nM in lots of different papers, this meaning that LSD tends to occupy 2A and 2C more than 2B. This is important because 5HT2B receptors are involved in cardiovascular signaling.
That said, DOB's highest binding affinity is for 5HT2B, and DOI prefers 2C to 2A, so this isn't everything. The NBOMe compounds highly favor 2A and 2C, but we all know that they can still be highly dangerous. Harmine binds to 5HT2A with a reported Ki of ~150nM, but I know I’ve never really experienced psychoactive effects from it. Then you get stuff like 3,4,5-TMA which have crap binding affinities for 5HT2A but are still active. There's a reason that the only way to know is by tasting tiny amounts and increasing slowly over time.
Earlier this year, a
paper came out in ACS where multiple new beta-carboline compounds were screened for binding and downstream activation of 5HT2A, 2B, and 2C receptors. Out of the linked paper, many potential serotonin receptor agonists emerged. The authors identified one in particular (compound 106) for followup; a beta-carboline with a chlorine at what would be the 5 position on the tryptamine and a 2,4,5 mexthoxybenzene hanging off the carbon connecting the terminal amine to the indole stimulates 5HT receptors in calcium flux assays: EC50s of 1.7, 0.58, and 0.50 nM at 5HT2A, 5HT2B, and 5HT2C. Ki values are in the 100-25 nM range for 2A and 2C, 3nM for 2B. My guess would be that it binds pretty well (Ki values for 2A and 2C are in the psilocyin range), but does a good job turning on the receptor once there. Looking deeper into it, this even appears to interact with the tryptophan toggle that is key for 5HT2A activation, similar to LSD and the NBOMe series. Promising stuff.
The reason that this is interesting is that the synthesis is relatively straightforward through the Pictet Spengler reaction: hold the tryptamine core you are interested in at 70-100C with whatever aldehyde you want to see next to the terminal amine (in either protic or aprotic solvent, doesn't appear to matter much) and you have your beta-carboline product. The supplementary data for the Orr paper gives synthesis details for around 100 compounds if anyone would like to follow up, I don't know if any human tasted any of these, they haven’t even been through head twitch tests.
There were some other products from the Orr paper that stick out - compounds 17, 22, 87, 91, 93, 94, and 103 also had EC50 values below 100nM for calcium flux activation. All appear to have similar affinity for 2A and 2C. There are others that appear effective at concentrations that could plausibly be reached in plasma, but these stick out. Compound 65 is interesting for activating 2A at reasonable concentrations and 2C at much higher concentrations while having high yield in microwave synthesis setups. Compound 79 appears high yield and highly selective for 2A, but has an EC50 in the 400nM range. (no Ki given, I don't think it was submitted to the Psychoactive Drug Screening Program)
Food for thought - a decent number of these are going to end up being psychoactive if they can get to the brain, but I have no clue as to the off-target effects, they could inhibit all sorts of enzymes for all we know. As far as metabolism goes, they are likely to be semi-difficult for our enzyme systems to inactivate. Other beta-carbolines that we have information on people consuming have long-ish half-lives. Harmine/Harmaline/Tetrahydroharmine I think are all around 12-18 hours, I know tadalafil is similar. For those showing particularly low EC50 values, effective dosages may be in the low microgram range or in the 100mg range depending on what exactly happens in the space between your tongue (or blood I guess if someone were to do IV) and your synapses.
