Cover Page The handle http://hdl.handle.net/1887/29763 holds various files of this Leiden University dissertation Author: Zweemer, Annelien Title: The ins and outs of ligand binding to CCR2 Issue Date: 2014-11-20 The INS and OUTS of ligand binding to CCR2 Annelien Jacomina Maria Zweemer The research described in this thesis was performed at the Division of Medicinal Chemistry of the Leiden Academic Centre for Drug Research, Leiden University (Leiden, The Netherlands). The research was part of the TI-Pharma initiative “Target residence time in translational drug research: the CCR2 chemokine receptor as a case in point” (Project number D1-301), in collaboration with Vertex Pharmaceuticals (San Diego, CA, USA) and the Vrije Universiteit Amsterdam (Amsterdam, The Netherlands). This thesis was printed by Gildeprint (Enschede, The Netherlands). The printing of this thesis was financially supported by PeproTech. Cover design: Esmee Gramberg - www.annageemag.com © Annelien Zweemer 2014. All rights reserved. No part of this thesis may be reproduced in any form without the prior written permission of the holder of copyright. The INS and OUTS of ligand binding to CCR2 Proefschrift ter verkrijging van de graad van Doctor aan de Universiteit Leiden, op gezag van Rector Magnificus prof. mr. C.J.J.M. Stolker, volgens besluit van het College voor Promoties te verdedigen op 20 november 2014 klokke 16:15 uur door Annelien Jacomina Maria Zweemer geboren te Goes in 1985 Promotiecommissie Promotor: Prof. Dr. A.P. IJzerman Co-Promotor: Dr. L.H. Heitman Overige Leden: Prof. Dr. M.M. Rosenkilde Prof. Dr. B. van de Water Prof. Dr. J. Kuiper Prof. Dr. P.H. van de Graaf Contents Chapter 1 General introduction Chapter 2 Bias in chemokine receptor signalling 23 Chapter 3 Multiple binding sites for small molecule antagonists at the chemokine receptor CCR2 45 Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2 71 Allosteric modulation of the chemokine receptor CCR2 by amiloride analogues and sodium ions 97 Structure-kinetics relationships – an overlooked parameter in hit-tolead optimization: a case of cyclopentylamines as CCR2 antagonists 121 Conclusions and future perspectives 143 Summary 159 Samenvatting 163 List of publications 169 Curriculum Vitae 173 Acknowledgements 177 Chapter 4 Chapter 5 Chapter 6 Chapter 7 7
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