title: Structure-activity relationships of quinoxaline-based 5-HT3A and 5-HT3AB receptor-selective ligands.
abstract: Until recently, discriminating between homomeric 5-HT3A and heteromeric 5-HT3AB receptors was only possible with ligands that bind in the receptor pore. This study describes the first series of ligands that can discriminate between these receptor types at the level of the orthosteric binding site. During a recent fragment screen, 2-chloro-3-(4-methylpiperazin-1-yl)quinoxaline (VUF10166) was identified as a ligand that displays an 83-fold difference in [(3)H]granisetron binding affinity between 5-HT3A and 5-HT3AB receptors. Fragment hit exploration, initiated from VUF10166 and 3-(4-methylpiperazin-1-yl)quinoxalin-2-ol, resulted in a series of compounds with higher affinity at either 5-HT3A or 5-HT3AB receptors. These ligands reveal that a single atom is sufficient to change the selectivity profile of a compound. At the extremes of the new compounds were 2-amino-3-(4-methylpiperazin-1-yl)quinoxaline, which showed 11-fold selectivity for the 5-HT3A receptor, and 2-(4-methylpiperazin-1-yl)quinoxaline, which showed an 8.3-fold selectivity for the 5-HT3AB receptor. These compounds represent novel molecular tools for studying 5-HT3 receptor subtypes and could help elucidate their physiological roles.
authors: Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors: Andrew J
authors: AJ
authors: Thompson
authors: Mark H P
authors: MH
authors: Verheij
authors: Jacqueline E
authors: JE
authors: van Muijlwijk-Koezen
authors: Sarah C R
authors: SC
authors: Lummis
authors: Rob
authors: R
authors: Leurs
authors: Iwan J P
authors: IJ
authors: de Esch
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3
references: J Biol Chem. 2005 May 27;280(21):20476-82
references: 15781467
references: J Mol Biol. 2012 Oct 5;422(5):617-634
references: 22841691
references: Brain Res Mol Brain Res. 2003 Nov 26;119(2):207-12
references: 14625088
references: EMBO J. 2009 Oct 7;28(19):3040-51
references: 19696737
references: Bioorg Med Chem Lett. 2004 Apr 19;14(8):1849-53
references: 15050614
references: J Biol Chem. 1999 Feb 26;274(9):5537-41
references: 10026168
references: Q Rev Biophys. 2010 Nov;43(4):449-99
references: 20849671
references: Pharmacogenomics. 2008 May;9(5):501-4
references: 18466097
references: Bioorg Med Chem Lett. 2010 Nov 15;20(22):6773-6
references: 20851599
references: J Med Chem. 1990 Jun;33(6):1594-600
references: 2342053
references: J Med Chem. 1997 Oct 24;40(22):3670-8
references: 9357534
references: Bioorg Med Chem Lett. 2004 Oct 18;14(20):5179-81
references: 15380223
references: J Med Chem. 2012 Oct 25;55(20):8603-14
references: 23006041
references: J Biol Chem. 2004 May 28;279(22):23294-301
references: 14998995
references: Biochemistry. 2008 Jun 17;47(24):6370-7
references: 18498149
references: Trends Pharmacol Sci. 2008 Sep;29(9):437-44
references: 18597859
references: J Med Chem. 1993 Sep 17;36(19):2745-50
references: 8410988
references: J Biol Chem. 1999 Oct 22;274(43):30799-810
references: 10521471
references: Pharmacol Biochem Behav. 1991 Dec;40(4):1033-40
references: 1816557
references: J Pharmacol Exp Ther. 2012 May;341(2):350-9
references: 22306960
references: J Physiol. 2011 Sep 1;589(17):4243-57
references: 21708905
references: J Med Chem. 2009 Nov 12;52(21):6946-50
references: 19831400
references: J Med Chem. 2008 Apr 24;51(8):2457-67
references: 18357976
references: Biochemistry. 2002 Aug 13;41(32):10262-9
references: 12162741
references: Chem Pharm Bull (Tokyo). 2009 Jan;57(1):34-42
references: 19122313
references: Expert Opin Ther Targets. 2007 Apr;11(4):527-40
references: 17373882
references: BMC Biochem. 2002 Jun 13;3:16
references: 12079499
references: J Neurosci. 2004 Oct 13;24(41):9097-104
references: 15483128
references: Mol Pharmacol. 2005 Aug;68(2):365-71
references: 15914697
references: J Biol Chem. 2008 Mar 14;283(11):6826-31
references: 18187416
references: Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
references: 4202581
references: Nature. 2003 Jul 17;424(6946):321-4
references: 12867984
references: Bioorg Med Chem. 2002 Mar;10(3):779-801
references: 11814868
references: Biol Pharm Bull. 2004 Sep;27(9):1403-5
references: 15340227
references: Biophys J. 2008 Dec 15;95(12):5728-36
references: 18931259
references: Pharmacol Ther. 2010 Oct;128(1):146-69
references: 20621123
references: Mol Pharmacol. 2011 Jul;80(1):183-90
references: 21505038
references: Curr Pharm Des. 2006;12(28):3615-30
references: 17073663
references: J Med Chem. 1993 Sep 3;36(18):2645-57
references: 8410977