Design, Synthesis, and Structure-Activity Relationships of Highly Potent 5-HT(3) Receptor Ligands

M.H.P. Verheij, Andrew J Thompson, Jacqueline E. van Muijlwijk-Koezen, S.C.R. Lumnis, R. Leurs, I.J.P. de Esch

Research output: Contribution to JournalArticleAcademicpeer-review

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-HT3R 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-HT3R 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 (pKi > 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.
Original languageEnglish
Pages (from-to)8603-8614
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number20
Early online date12 Oct 2012
DOIs
Publication statusPublished - 25 Oct 2012

Bibliographical note

Working title: Quinazolines and (iso)quinolines as potent 5HT3 ligands.

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