Chemistry and Structure-Activity Relationships of Psychedelics

Introduction

Nichols frames the chapter as a synthesis of structure–activity relationships (SAR) for the classic serotonergic hallucinogens, focusing on the three principal chemotypes: tryptamines, ergolines and phenethylamines. Earlier work established that many classic psychedelics are agonists or partial agonists at the serotonin 5-HT2A receptor, which is central to cortical function and cognition; however, for many older compounds receptor affinity and functional data are sparse and much evidence still rests on animal behavioural assays and smooth muscle tests. The author emphasises that modern molecular pharmacology and renewed clinical interest make revisiting and integrating SAR important for both theoretical understanding and practical implications. This chapter sets out to identify structural features that determine psychedelic activity across the three chemotypes, to compare commonalities where possible, and to relate behavioural, biochemical and molecular pharmacology data. Nichols signals reliance on a mix of early human anecdotes, animal models (drug discrimination, head-twitch, rabbit hyperthermia, etc.), receptor binding and functional assays, in silico docking, and mutagenesis studies to build the SAR picture. Compounds that act at targets other than 5-HT2A (for example, MDMA, salvinorin A, ketamine, cannabinoids) are explicitly excluded from the discussion.