Design, Synthesis, and Structure–Activity Relationships of Highly Potent 5‑HT3 Receptor Ligands

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–activi...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2012-10, Vol.55 (20), p.8603-8614
Main Authors: Verheij, Mark H. P, Thompson, Andrew J, van Muijlwijk-Koezen, Jacqueline E, Lummis, Sarah C. R, Leurs, Rob, de Esch, Iwan J. P
Format: Article
Language:English
Subjects:
Binding, Competitive
Computer Simulation
Drug Design
HEK293 Cells
Humans
Isoquinolines - chemical synthesis
Isoquinolines - chemistry
Isoquinolines - pharmacology
Ligands
Models, Molecular
Quinazolines - chemical synthesis
Quinazolines - chemistry
Quinazolines - pharmacology
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Radioligand Assay
Receptors, Serotonin, 5-HT3 - metabolism
Stereoisomerism
Structure-Activity Relationship
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Summary: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 (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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300801u