Discovery and characterization of antidepressant mediated activation of 5-HT1E and 5-HT1F receptors.

Abstract

Of the 13 serotonin (5-hydroxytryptamine, 5-HT) receptors in humans, the 5-HT1E and 5-HT1F subtypes (1E and 1F, respectively), are understudied G protein-coupled receptors with high sequence identity among themselves, and to a lesser degree, the other 5-HT1 receptor subtypes. While 1F is a validated target for anti-migraine drugs, the physiological function of 1E remains unknown due to a lack of rodent orthologs and selective compounds. To expand the repertoire of potential chemical scaffolds that could be used to generate 1E- and 1F-selective compounds, we screened a small library of medications and research compounds with known activities at various aminergic receptors. This screen led us to discover that a series of clinically-used drugs featuring a tetracyclic scaffold are high-affinity agonists at 1E and 1F, while they have generally been reported as pan-aminergic antagonists. Seeking to elucidate their mechanisms, we determined structures of 5-HT1E complexed with Gi1 and bound by two of these drugs at 3.31 and 3.28 Å. These structures reveal unambiguous binding poses that demonstrate key interactions with binding pocket residues that confer high affinity in a ligand-specific fashion, and lay the stage for the generation of 1E-specific agonists for physiological studies. Additionally, our functional work offers a putative mechanism of action for the reported anti-migraine activities of the medications characterized in this study.