title: Design, synthesis, and structure-activity relationships of highly potent 5-HT₃ receptor ligands.
abstract: The 5-HT₃ receptor, a pentameric ligand-gated ion channel (pLGIC), is an important therapeutic target. During a recent fragment screen, 6-chloro-N-methyl-2-(4-methyl-1,4-diazepan-1-yl)quinazolin-4-amine (1) was identified as a 5-HT₃ hit fragment. Here we describe the synthesis and structure-activity relationships (SAR) of a series of (iso)quinoline and quinazoline compounds that were synthesized and screened for 5-HT₃ R affinity using a [³H]granisetron displacement assay. These studies resulted in the discovery of several high affinity ligands of which compound 22 showed the highest affinity (pK(i) > 10) for the 5-HT₃ receptor. The observed SAR is in agreement with established pharmacophore models for 5-HT₃ ligands and is used for ligand-receptor binding mode prediction using homology modeling and in silico docking approaches.
authors.affiliation: Leiden/Amsterdam Center of Drug Research-LACDR, Amsterdam Institute for Molecules Medicines and Systems-AIMMS, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Mark H P
authors.initials: MH
authors.lastname: Verheij
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: van Muijlwijk-Koezen
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
mesh_terms: D001667:Binding, Competitive; D003198:Computer Simulation; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D008024:Ligands; D011799:Quinazolines; D011804:Quinolines; D044406:Receptors, Serotonin, 5-HT3