Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.
Opioids, cannabinoids, and psychedelics all act by binding to G protein-coupled receptors (GPCRs), which mediate their inebriating, lethal, and therapeutic effects. Recent structural studies reveal the molecular mechanisms of drugs like fentanyl, tetrahydrocannabinol, and lysergic acid diethylamide at their respective GPCR subtypes. These insights facilitate drug discovery, both for developing treatments to combat substance abuse and for harnessing the therapeutic potential of certain drugs.