Molecular insights into GPCR mechanisms for drugs of abuse

Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R

“…Within the 5-HT 1e R ligand binding pocket, mianserin and setiptiline exhibit similar topologies, adopting an open C-shaped bend across their tricyclic moieties and forming a conserved salt bridge between a tertiary amine in their fourth ring and D102 3.32 ( Fig. 3 ) ( 37 ). The piperazine ring of mianserin (analogously the tetrahydropyridine ring of setiptiline) resides near the conserved residues F307 6.51 and Y334 7.43 , which form one end of the orthosteric binding pocket.…”

“…4B ). The two ligands also formed a stable π-π stacking interaction with F308 6.52 via the benzyl group of the tricyclic scaffold, as well as a hydrogen bond and a salt bridge with the side chain of D102 3.32 via their piperazine nitrogen, which are typically present in aminergic GPCRs ( 36 , 37 ). The most notable difference between the two ligands was an interaction formed with a probability larger than 30% by mianserin, but not setiptiline, with residue H177 ECL2 .…”

“…5A ). As is the case for mianserin, both methiothepin and zotepine are anchored to their respective 5-HTRs via a conserved salt bridge with D 3.32 ( 37 ), and their multicyclic moieties adopt a kinked C-shaped conformation occupying the amphipathic orthosteric binding pocket. However, the binding pose of both antagonists is fundamentally different, with both methiothepin and zotepine binding in a mirrored orientation compared to mianserin.…”