Abstract
Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use. Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) and d-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the nonhallucinogenic psychedelic analog lisuride. Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects. The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective nonhallucinogenic psychedelic analogs with therapeutic effects.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antidepressive Agents / chemistry
-
Antidepressive Agents / metabolism
-
Antidepressive Agents / pharmacology*
-
Arrestin / metabolism
-
Binding Sites
-
Crystallography, X-Ray
-
Drug Design*
-
Hallucinations / chemically induced
-
Hallucinogens / chemistry*
-
Hallucinogens / metabolism
-
Hallucinogens / pharmacology*
-
Heterocyclic Compounds, 4 or More Rings / chemistry
-
Humans
-
Ligands
-
Lisuride / chemistry
-
Lisuride / metabolism
-
Lysergic Acid Diethylamide / chemistry
-
Lysergic Acid Diethylamide / metabolism
-
Mice
-
Protein Conformation
-
Psilocybin / analogs & derivatives
-
Psilocybin / chemistry
-
Psilocybin / metabolism
-
Receptor, Serotonin, 5-HT2A / chemistry*
-
Receptor, Serotonin, 5-HT2A / metabolism
-
Serotonin / chemistry
-
Serotonin / metabolism
-
Signal Transduction
-
Structure-Activity Relationship
Substances
-
Antidepressive Agents
-
Arrestin
-
Hallucinogens
-
Heterocyclic Compounds, 4 or More Rings
-
Ligands
-
Receptor, Serotonin, 5-HT2A
-
Psilocybin
-
Serotonin
-
lumateperone
-
Lysergic Acid Diethylamide
-
psilocin
-
Lisuride