Structural pharmacology and therapeutic potential of 5-methoxytryptamines

Summary & key facts

Scientists mapped how a class of tryptamine psychedelics, including 5-methoxy-DMT and LSD, stick to and switch on a brain receptor called 5-HT1A. They used high-resolution molecular imaging to see drug–receptor contacts and then made related compounds. In mice, one modified compound that strongly targets 5-HT1A did not cause hallucinatory-like behaviours but still showed anxiety- and depression-like benefits. The work explains at an atomic level how these drugs act and suggests a way to make new medicines that target 5-HT1A, while noting that human evidence for 5-methoxy-DMT so far mainly comes from surveys and early reports.

Key facts:

• The team imaged 5-HT1A receptors bound to 5-methoxy-DMT and LSD using cryo-electron microscopy, which lets researchers see molecules at near-atomic detail (about 3 angstroms resolution).
• In cell tests, many tryptamine psychedelics acted as strong activators of 5-HT1A signalling, meaning they turn on the receptor in a way similar to the brain chemical serotonin.
• The structures showed that 5-methoxy-DMT and LSD sit a bit deeper in the 5-HT1A binding pocket than serotonin and make a specific hydrogen bond that likely changes how the receptor moves and signals.
• Using medicinal chemistry, the researchers made a 5-methoxytryptamine analogue that is selective for 5-HT1A and, in mice exposed to social stress, it reduced anxiety-like and depression-like behaviours without producing hallucinatory-like responses.
• The study compares how drugs act at two serotonin receptors, 5-HT1A and 5-HT2A, and finds that LSD and 5-methoxy-DMT activate both receptors at similar strengths in lab assays.
• The paper notes that most human reports about therapeutic effects of 5-methoxy-DMT come from open-label trials and surveys, which are less reliable than controlled clinical trials.
• The molecular details in this work could help scientists design new drugs that target 5-HT1A for conditions linked to mood and anxiety, but the findings in cells and mice do not prove safety or effectiveness in people yet.

Topics

Chemical synthesis and alkaloids Phenothiazines and Benzothiazines Synthesis and Activities Psychedelics and Drug Studies

Categories

Clinical Psychology Psychology Social Sciences

Tags

Biology Clinical pharmacology Computational biology Medicine Pharmacology

Substances

Ayahuasca LSD Other Psilocybin

Conditions & symptoms

Anxiety Depression PTSD Substance abuse disorder Anxiety or worry Sadness or low mood