Researchers at the University of California, Davis have used systematic chemical deconstruction of lysergic acid diethylamide (LSD) to identify which features of its complex molecular architecture are required to produce its characteristic activity at serotonin receptors — findings the authors say will aid efforts to develop LSD-based therapeutics with improved safety and efficacy profiles, according to a study published in PNAS.
LSD's tetracyclic ergoline core has long complicated structure–activity relationship studies, making it difficult to determine which parts of the molecule drive its pharmacology and which are dispensable. The UC Davis team applied function-oriented synthesis — a strategy that systematically strips away structural complexity to identify the minimal features required for biological activity — to generate nine simplified analogues, termed ergologs, ranging from monocyclic to tricyclic variants of the ergoline scaffold.
The ergologs were characterized for binding and functional activity at 5-HT2A, the primary receptor mediating LSD's psychedelic effects, as well as at 5-HT2B, 5-HT2C, and dopamine D2 receptors. Gq activation, β-arrestin2 recruitment, and hallucinogenic potential were assessed in vitro, while mouse studies measured head-twitch response, amphetamine-induced hyperlocomotion, and pharmacokinetics. Molecular docking provided structural context for the receptor-binding data.
A tricyclic ergolog, UCD0094, retained meaningful 5-HT2A activity while producing approximately 52% Gq Emax and did not induce a head-twitch response in mice, suggesting a non-hallucinogenic profile in the assays used. Further simplification to bicyclic and monocyclic variants progressively reduced potency and receptor selectivity. Stereochemical analysis also showed enantioselectivity at 5-HT2A, consistent with LSD's stereospecific receptor binding.