4-Desmethylene-LSD

Pharmacodynamics

Like LSD, the drug is known to be a highly potent serotonin 5-HT_2A and 5-HT_2C receptor agonist in vitro.^[1] Its affinities (IC₅₀Tooltip half-maximal inhibitory concentration) are in the ranges of 10–100 nM for the serotonin 5-HT_2A receptor and 100–1,000 nM for the serotonin 5-HT_2C receptor, while its activational potencies (EC₅₀Tooltip half-maximal effective concentration) are less than 10 nM for the serotonin 5-HT_2A receptor and in the range of 10–100 nM for the serotonin 5-HT_2C receptor.^[1] 4-Desmethylene-LSD was the most potent serotonin 5-HT_2A receptor agonist of 27 evaluated ergoline-like compounds.^[1] In line with its serotonin 5-HT_2A receptor agonism, and similarly to LSD and other psychedelics,^[3][4] 4-desmethylene-LSD has been found to produce psychoplastogenic effects on neurite growth in vitro.^[1]

Many serotonin 5-HT_2A receptor agonists, for instance LSD, produce psychedelic effects in humans.^[1][5][6][7] The publication that reported 4-desmethylene-LSD specifically pertained to psychoplastogenic ergoline-like compounds with no or reduced hallucinogenic activity for potential therapeutic use.^[1] However, the hallucinogenic-related properties of 4-desmethylene-LSD and the other reported compounds, for instance their effects in the head-twitch response (HTR) assay, were not individually described.^[1] As such, it remains unclear whether or not 4-desmethylene-LSD could have psychedelic effects in humans.^[1]

Related compounds

Other related compounds in which one or more other carbons have been removed from the LSD's ergoline ring system to produce simplified and less-rigid phenethylamines and tryptamines include N-DEAOP-NMT (desvinyl-LSD)^[8][9] and NDTDI (9-desmethine-LSD).^[10][11][12] Desvinyl-LSD is the analogue of LSD in which the carbon atoms at positions 9 and 10 of the ergoline ring system have been removed to make a fully non-rigid tryptamine,^[8][9] while 9-desmethine is the analogue of LSD in which the methine at position 9 has been removed to make a rigid tricyclic tryptamine.^[10][11][12] Desvinyl-LSD has been found to produce LSD-like effects in rodents,^[8][9] while 9-desmethine-LSD has been encountered as a novel recreational and designer drug and made illegal in parts of Europe.^[10][11]

The analogue of 4-desmethylene-LSD without the ethyl groups on the amide has been described.^[8][13] In addition, 4-desmethylene-LSD's analogue without the amide ethyl groups and with a phenyl ring instead of the indole ring has been described.^[8][13] Their activities were not reported.^[8][13]

WXVL_BT0793LQ2118, an analogue of 4-desmethylene-LSD lacking the N,N-diethyl-carboxamide moiety and with a fluorine at the 6-position, has been reported.^[14][15] It was identified via in silico screening of 1.6 billion molecules for serotonin 5-HT_2A receptor agonism with AlphaFold2.^[14] Following identification, the drug was assessed and found to be a potent serotonin 5-HT_2A, 5-HT_2B, and 5-HT_2C receptor agonist.^[14]