Effect of Bulky N-Dibenzofuranylmethyl Substitution on the 5-HT2 Receptor Affinity and Efficacy of a Psychedelic Phenethylamine.
ACS Chemical Neuroscience February 7, 2024 Breno A. Soares, Thirumal Yempala, Darío Martínez-afani et al. 4 citations
Adding a very large chemical group (dibenzo[b,d]furylmethyl, or DBFM) to the nitrogen atom of the psychedelic phenethylamine 2C-B can either decrease or increase its binding to serotonin 5-HT2 receptors, depending on which position of the DBFM group is attached. Attaching through the 4-position generally improved affinity, with one compound showing 10-fold higher affinity at 5-HT2A receptors and 40-fold higher at 5-HT2C receptors, though selectivity among receptor subtypes was low. All compounds were weak partial agonists at 5-HT2A receptors but full or nearly full agonists at 5-HT2C receptors. Molecular docking simulations indicated the dibenzofuryl part inserts deeper into the 5-HT2A receptor's binding site than into 5-HT2C's, interacting with a key activation switch.