Dibenzofuranylethylamines as 5-HT2A/2C Receptor Agonists

Abstract

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-HT_2A and 5-HT_2C 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-HT_2C 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 Ala222^5.46 residue in the 5-HT_2C receptor to the larger Ser242^5.46 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 Phe^6.52 residue and breaks a hydrogen bond between the dibenzofuran oxygen and Ser^5.43, 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 and substance abuse.

Figure 1

Structures of serotonin and 2,5-dioxygenated-4-substituted serotonin receptor ligands.

Figure 2

Structures of carbazole-derived beta blockers.

Figure 3

Dibenzofuranylethylamines synthesized and tested in this work.

Scheme 1. DBF: Variously Substituted Dibenzo[b,d]furans

(a) AcOH/AcO^–NH₄⁺, reflux, 4 h, 84–88%. (b) THF, reflux, 16 h, then HCl/acetone, 65–72%.

Figure 4

Overlaid crystal structure of the 5-HT_2C receptor (cyan) and model of the 5-HT_2A receptor (yellow-tan). The bound ergoline in the crystal is shown in magenta. Nonconserved residues are shown as sticks.

Figure 5

Key interactions of 5 in the orthosteric binding site of 5-HT_2C and 5-HT_2A receptors (colored slate blue). Nonconserved residues in 5-HT2_C/2A receptors at position 5.46 (yellow for A222^5.46 in 5-HT_2C (A) and cyan for S242^5.46 (B) in 5-HT_2A, respectively). According to our docking results, this difference results in a significant weakening of the π–π interaction with F6.52 and of the hydrogen bond between the dibenzofuranyl oxygen atom and S5.43.

Figure 6

Comparison of the structures of compound 3, 2C-phenyl, and “Fly” (with dihydrofuran rings) and “Dragonfly” compounds (with furan rings).