Selective 5-HT2AR agonism without 5-HT2BR activation is critical for safe psychedelic-inspired therapeutics. Here, we systematically probe the ligand-binding pockets of 5-HT2AR and 5-HT2BR and identify steric and conformational constraints at the side-extended pocket (SEP) and extended binding pocket (EBP) that dictate ligand orientation and receptor signaling. Guided by these insights, we...
Classical psychedelics exert hallucinogenic and therapeutic effects primarily through activation of serotonin 2 A receptor (5-HT2AR), offering promise as transformative treatments for neuropsychiatric disorders. However, their concurrent activation of 5-HT2BR—associated with cardiac valvulopathy—raises serious safety concerns, underscoring the need for subtype-selective psychedelics. To address...
Understanding the kinetics of LSD in receptors and subsequent induced signaling is crucial for comprehending both the psychoactive and therapeutic effects of LSD. Despite extensive research on LSD's interactions with serotonin 2A and 2B receptors, its behavior on other targets, including dopamine receptors, has remained elusive. Here, we present cryo-EM structures of LSD/PF6142-bound dopamine...