Journal of Medicinal Chemistry · 2004 · 60 citations · 28 references
MedicineMedicinal ChemistryPharmacologyMolecular PharmacologyPharmacophore ModelingStructure-activity RelationshipsDrug-receptor InteractionsLigand BindingMolecular ModelingReceptor BindingReceptor PharmacologyReceptor-ligand InteractionsAdenylate Cyclase RegulationAdenylate Cyclase SignalingAgonist ActivityChemical Structure-activity RelationshipsG Protein-coupled Receptor ModelingPharmacophore Model ConstructionPharmacophore Model RefinementStructure-activity Relationship Modeling
A series of arylpiperazine- and 1,2,3,4-tetrahydroisoquinoline-based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active 5-HT7 receptor. Effects on basal adenylate cyclase activity were measured using HEK-293 cells expressing the rat 5-HT7. All ligands produced a decrease of adenylate cyclase activity, indicative of their inverse agonism. Additionally, computational studies with a set of 22 inverse agonists, including these novel inverse agonists and inverse agonists known from literature, resulted in a pharmacophore model and a CoMFA model (R2 = 0.97, SE = 0.18). Docking of inverse agonists at the binding site of a model of the helical parts of the 5-HT7 receptor, based on the alpha carbon template for 7-TM GPCRs, revealed interesting molecular interactions and a possible explanation for observed structure-activity relationships.
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