Deconstruction of lysergic acid diethylamide

Of the classic psychedelics, lysergic acid diethylamide (LSD) is perhaps the best-known, but its complex chemical architecture has limited synthetic investigations aimed at generating analogues with improved safety and efficacy profiles. Here, we systematically deconstruct the tetracyclic ergoline core of LSD to create 9 simplified ergoline analogues (i.e., ergologs) and evaluate them in pharmacological assays relevant to 5-HT2A, 5-HT2B, and 5-HT2C receptor function. Our work revealed the key molecular features and minimal pharmacophore of LSD necessary to produce maximal agonism of 5-HT2A receptors and hallucinogenic behavioral effects. Furthermore, we established strategies for reducing the hallucinogenic and cardiotoxic potential of LSD and identified UCD0094 and UCD0076 as ergologs with improved safety profiles. In stark contrast to LSD, UCD0076 exhibits preference for activating 5-HT2C receptors over other 5-HT2 receptors and produces antipsychotic-like properties in mouse behavioral assays.