Journal of medicinal chemistry

A Drug-Friendly Water-Repelling Pathway in the 5-HT2A Receptor Targeted by Powerful Phenethylamines

Updated

Abstract

Agonist potencies at the 5-HT2A receptor were shown to increase with analogs having substituents at C-4 of the phenyl ring containing at least four heavy atoms.

  • The serotonin 2A receptor is the most prevalent excitatory serotonin receptor in the brain.
  • A hydrophobic tunnel adjacent to the orthosteric site was identified in experimental structures of the receptor.
  • Molecular modeling and functional characterization were used to investigate the tunnel's role in receptor pharmacology.
  • Substituents at C-4 of the phenyl ring in phenethylamine analogs can interact with the identified tunnel.
  • These findings suggest that the tunnel may serve as a potential target for drug development.

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