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A set of 31 diversified 5-HT7receptor antagonists was automatically docked to a conformational ensemble of rhodopsin-based 5-HT7R models (flexible docking). It was found that ergolines, aporphines, and tricyclic psychotropic agents were always docked in a pocket formed by TMHs 4-6, and besides the main ionic bond with Asp3.32, they had specific interactions with Phe6.52, Phe6.51, Trp6.48, and Ser5.42. The arylpiperidine, arylpiperazine, or -carboline fragment of the complex ligands occupied the same pocket, whereas the terminal amide/imide part of those compounds reached the second cavity formed by TMHs 7-3 and interacted with Phe3.28, Arg7.36, and Tyr7.43. A similar orientation of selective antagonists of the group of arylsulfonamidoalkylamines was observed, that is, the sulfonamide part was located in the second pocket. Coherent docking results allowed the generation of two receptor-based pharmacophores:? first containing features necessary for high 5-HT7R affinity and the other defining selectivity for this receptor subtype. The latter model indicated the importance of specific interactions with the residues of the TMHs 7-3 pocket (especially nonconserved Arg7.36) for selectivity over other monoamine GPCRs.