The 5HT2AR receptor, a G-protein-coupled receptor targeted by psychedelic drugs, collapses to a closed active state without Gqα, revealing an intermediate partially-open conformation. Molecular dynamics simulations and free-energy calculations show that serotonin and psilocin bind more tightly to the orthosteric pocket than to the extended binding pocket. These findings clarify activation mechanisms and may guide development of novel therapeutics for neurological and psychiatric disorders.
Phencyclidine (PCP) and its analogues block the open state of the NMDA receptor channel in hippocampal neurons, reducing the frequency and duration of ion channel openings. This blockade is voltage-dependent, reversed at positive membrane potentials. A behaviorally inactive analogue left NMDA-activated currents relatively unaltered, while m-nitro-PCP at low concentrations unexpectedly increased opening frequency, suggesting that modifications to the PCP molecule can enhance rather than decrease excitability.