title: Synthesis, testing and structure-activity studies on a library of 5-HT₄ ligands.
abstract: Several indole derivatives and analogues comprising a range of related structural classes were designed, synthesized and tested as ligands for the 5-HT₄ receptor. Within each series, binding experiments showed compounds with good affinity demonstrating high percentage displacement values at 1 µM. The most potent of these (20) had a pKi of 8.54 demonstrating very good affinity. These indole analogues were combined with 55 ligands that were previously produced in our laboratory to explore the structure-activity relationships of these 5-HT₄ ligands. A CoMFA (Comparative Molecular Field Analysis) analysis was used to extend an earlier simple pharmacophore to suggest two new molecular features beyond the primary amino binding site. The pharmacophore confirmed that a newly described tetrahydroquinoline analogue was able to match the basic requirements of the model and the pharmacology of this molecule is provided in more detail.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Amir
authors.initials: A
authors.lastname: Hanna-Elias
authors.forename: David T
authors.initials: DT
authors.lastname: Manallack
authors.forename: Alla
authors.initials: A
authors.lastname: Levit
authors.forename: William
authors.initials: W
authors.lastname: Nguyen
authors.forename: Fadi
authors.initials: F
authors.lastname: Ayad
authors.forename: Glen
authors.initials: G
authors.lastname: Perera
authors.forename: Marina
authors.initials: M
authors.lastname: Shapiro
authors.forename: Helen R
authors.initials: HR
authors.lastname: Irving
authors.forename: Ian M
authors.initials: IM
authors.lastname: Coupar
authors.forename: Magdy N
authors.initials: MN
authors.lastname: Iskander
mesh_terms: D001665:Binding Sites; D007700:Kinetics; D008024:Ligands; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D044422:Receptors, Serotonin, 5-HT4