Quinazolines and (iso)quinolines as potent 5HT3 ligands

Jacqueline E. van Muijlwijk-Koezen, M.H.P. Verheij, A.J. Thompson, August B Smit, 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
DOIs
Publication statusPublished - 24 Sep 2012

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Quinolines
Quinazolines
Receptors, Serotonin, 5-HT3
Granisetron
Ligands
Ligand-Gated Ion Channels
Computer Simulation
Amines
Therapeutics
quinoline

Cite this

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title = "Quinazolines and (iso)quinolines as potent 5HT3 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-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.",
author = "{van Muijlwijk-Koezen}, {Jacqueline E.} and M.H.P. Verheij and A.J. Thompson and Smit, {August B} and S.C.R. Lumnis and R. Leurs and {de Esch}, I.J.P.",
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doi = "10.1021/jm300801u",
language = "English",
volume = "55",
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journal = "Journal of Medicinal Chemistry",
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Quinazolines and (iso)quinolines as potent 5HT3 ligands. / van Muijlwijk-Koezen, Jacqueline E.; Verheij, M.H.P.; Thompson, A.J.; Smit, August B; Lumnis, S.C.R.; Leurs, R.; de Esch, I.J.P.

In: Journal of Medicinal Chemistry, Vol. 55, No. 20, 24.09.2012, p. 8603-8614.

Research output: Contribution to JournalArticleAcademicpeer-review

TY - JOUR

T1 - Quinazolines and (iso)quinolines as potent 5HT3 ligands

AU - van Muijlwijk-Koezen, Jacqueline E.

AU - Verheij, M.H.P.

AU - Thompson, A.J.

AU - Smit, August B

AU - Lumnis, S.C.R.

AU - Leurs, R.

AU - de Esch, I.J.P.

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AB - 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.

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