Simple Analogs of the LSD D-Ring: A Consideration of Structure–Activity Relationships and Their Potential as Therapeutics

Psychedelic drugs have begun to show therapeutic promise. However, there is a growing research effort focused on creating nonhallucinogenic analogs of these substances. The goal is to develop new treatments for an expanding list of psychiatric and neurodegenerative disorders, while eliminating the complications and costs of treatment engendered by the subjective psychedelic experience. Structure-activity relationships (SAR), particularly for LSD (d-lysergic acid diethylamide), have guided many of these efforts. This perspective examines the historical development and behavioral testing of several simple analogs of LSD's D-ring, which, while nonhallucinogenic and nontoxic within the context of their testing to date, can block the behavior-disrupting effects of psychedelics administered to rodents. However, these data are quite mature. D-ring analogs of LSD may have therapeutic potential but require further testing to examine binding, plastogenic effects, and potential utility in psychiatry and neuromedicine, and are ripe for reinvestigation with current tools, approaches, and concepts. Further, the SAR data strongly suggest that the incorporation of several changes to the structural elements of the D-ring may enhance the effects of other LSD-related analogs currently undergoing clinical trials.