RT Journal Article T1 Dibenzofuranylethylamines as 5-HT2A/2C Receptor Agonists A1 Yempala, Thirumal A1 Brea Floriani, José Manuel A1 Loza García, María Isabel A1 Matthies, Douglas J. A1 Zapata-Torres, Gerald A1 Cassels, Bruce K. K1 Agonists K1 Aromatic compounds K1 Crystal structure K1 Noncovalent interactions K1 Receptors AB The human 5-HT2 receptor subtypes have high sequence identity in their orthosteric ligand-binding domain, and many agonists are poorly selective between the 5-HT2A and 5-HT2C subtypes. Nevertheless, their activation is associated with different pharmacological outcomes. We synthesized five phenethylamine analogs in which the benzene ring is replaced by a bulky dibenzo[b,d]furan moiety and found a couple with >70-fold 5-HT2C selectivity. Molecular docking studies of the most potent compound (5) at both receptor subtypes revealed the likely structural basis of its selectivity. Although in both cases, some crucial interactions are conserved, the change of the Ala2225.46 residue in the 5-HT2C receptor to the larger Ser2425.46 in the 5-HT 2A subtype, which is the only structural difference between the orthosteric binding pockets of both receptors, weakens a π−π stacking interaction between the dibenzofuran moiety and the important Phe6.52 residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser5.43 , explaining the selectivity of compound 5 for the 5-HT 2C receptor. We believe that this effect of the residue at position 5.46 merits further exploration in the search for selective 5-HT 2C receptor agonists that are of considerable interest in the treatment of schizophrenia PB ACS YR 2020 FD 2020-01-27 LK https://hdl.handle.net/10347/45557 UL https://hdl.handle.net/10347/45557 LA eng NO ACS Omega 2020, 5, 5, 2260–2266 DS Minerva RD 24 abr 2026