Description
Why DM-506 over other Ibogaine derivative RC candidates
- In summary, the most potent non-hallucinogenic psychedelics in order is: DM-506 > Ibogainalog ∼ Noribogainalog > Catharanthalog > Zalsupindole > Tabernanthalog
- DM-506 lacks any HTR (head-twitch response) which is a unique response to hallucinogenic psychedelics like TCB-2 and DOI in mice; making DM-506 a non-hallucinogenic psychedelic [x]
- DM-506 is a significantly more potent 5-HT2A agonist (EC50 =
34 nM) than Ibogainalog and Tabernanthalog (EC50 =85 nM and1121 nM), making DM-506>30xmore potent than Tabernanthalog [x] - DM-506 has
>9x selectivity for 5-HT2A (Ki =19 ± 1 nM) over the undesirable 5-HT2C (Ki =176 ± 102 nM), while Ibogainalog and Tabernanthalog have much lower selectivity [x] - DM-506 has significantly higher blood brain barrier permeability (LogBBB =
0.76) than Tabernanthalog and Ibogainalog (LogBBB =0.65and0.62) [x]. Thus, DM-506 likely has higher neuronal permeability than Ibogainalog and Tabernanthalog by not having the added bulk of a Methoxy (MeO) or Hydroxy (HO) group. This is seen with DMT being more neuronally permeable than 5-MeO-DMT and Psilocin (4-HO-DMT), allowing greater intracellular 5-HT2A interaction [x] - Interestingly, DM-506 has a higher 5-HT2A affinity (Ki =
19 ± 1 nM) than DMT and Psilocin (Ki =Â127.0 nMand107.2 nM) [x, x]
Why DM-506 over the isoDMT derivative RC candidates
- In summary, both the parent compound, isoDMT, and its derivatives have far too weak 5-HT2A affinity to be chosen over the non-hallucinogenic Ibogaine derivatives
- Though the isoDMT derivatives are interesting non-hallucinogenic psychedelics, with Zalsupindole being the only active one without a MAOI, isoDMT has a low 5-HT2A affinity (Ki =
600 - 650 nM) [x] - There’s no available data on Zalsupindole‘s 5-HT2A affinity, it’s hard to believe it’s much better considering that 6-MeO-isoDMT, which is structurally the closest to Zalsupindole, has an even lower 5-HT2A affinity (Ki =
1040 nM) [x] - But Zalsupindole is described to having a similar and slightly improved ligand score over Tabernanthalog, both being far weaker than 5-F-DMT and 5-Cl-DMT, since Tabernanthalog has a quite low 5-HT2A affinity (Ki =
4440 ± 1519 nM) [x, x] - Therefore, Zalsupindole (AAZ-A-154) is too similar to the strength of Tabernanthalog (TBG), putting it no where near DM-506’s potency
- Candidates like 2-Br-LSD, Ariadne, or 6-F-DET weren’t considered because of their unecessarily larger structure, following the pattern that smaller molecules trend toward higher neuronally permeable, or containing the Phenethylamine structure, known to undesirably be β-arrestin biased at 5-HT2A [x]
Discussing DM-506 targets other than 5-HT2A/C
- DM-506 is a weak MAO-A (
16%inhibition at100 μM), SERT (IC50 =3.1 ± 0.4 μM), and NET (IC50 =9.5 ± 1.8 μM) inhibitor, as it’s in the μM range [x] - Structurally, DM-506 is in between DMT and Ibogaine
