Researching LSD

by Michael Pennington

Lysergic acid diethylamide, LSD, is a potent serotonin receptor binding molecule which is responsible for inducing strong and vivid hallucinations in humans. The molecule was first synthesized in 1938 as a derivative of ergotamine a naturally occurring alkaloid isolated from ergot fungus.  Initially, LSD was approved as drug and marketed by Sandoz as Delysid and prescribed in the late 1940’s for psychiatric care. During the 1960’s, LSD became a popular illicit drug to the counterculture present at that time and was ultimately responsible for its prohibition.

Recently, a group of researchers at the University of North Carolina at Chapel Hill lead by Dr. Bryan L. Roth have crystallized LSD in the human serotonin receptor 5-HT2B as reported in Cell ( ).The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slowly from both 5-HT2BR and 5-HT2AR—a major target for its psycho-activity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a lid comprised by extracellular loop 2 (EL2) at the entrance to the binding pocket. A point mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

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