Molecular dynamics study of differential effects of serotonin-2A-receptor (5-HT2AR) modulators

The serotonin-2A receptor (5-HT2AR) is an interesting target for drug design in the context of antidepressants that might have a rapid onset of action and/or be effective in treatment-resistant cases. The main challenge, however, is that the activation of this receptor can provoke hallucinations. Recent studies have shown that activating the receptor with certain (partial) agonists could potentially give rise to antidepressant effect without hallucinogenic side effects. Although substantial research has been done in this area, the atomistic details of this differential activation of the serotonin-2A receptor are not fully understood. In the present study we performed multiple atomistic molecular dynamics (MD) simulations on 5-HT2AR bound with an antipsychotic, two different potential non-hallucinogenic antidepressants and a hallucinogen to identify the receptor’s ligand dependent conformations. Overall, our findings suggest that modest 5-HT2AR activation would only yield antidepressant effects and hallucinations result from excessive activation. While modest activation through microdosing may be problematic on account of abuse potential as well as possibly narrow and patient-dependent therapeutic windows, modest activation through administration of a sufficiently weak partial agonist may offer a viable drug development pathway.