How Activation of 5-HT2A Receptors Differs from 5-HT2B Receptors

Cryo-EM structures reveal the binding of a selective 5-HT2AR agonist and 5-HT2BR antagonist.

• Selective activation of 5-HT2A receptors without engaging 5-HT2B receptors may enhance the safety profile of psychedelic-inspired therapeutics.
• Steric and conformational constraints at specific binding pockets are critical for ligand orientation and receptor signaling.
• Derivatives designed from tryptamine and phenethylamine scaffolds can improve 5-HT2A receptor activation while limiting 5-HT2B receptor activity.
• Differential activation mechanisms between 5-HT2A and 5-HT2B receptors were observed, supporting the design strategy for safer serotonergic compounds.

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