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Chapter 2 Scope of this thesis The histamine H4 receptor (H4R) is currently seen as a potential drug target for treating diseases like asthma, allergic rhinitis and pruritis. 1-4 Design of novel, high affinity and selective H4R ligands is therefore of considerable interest. 1, 5, 6 This new histamine receptor was reported to be expressed mainly in bone marrow, peripheral blood, spleen, thymus, small intestine, colon, heart, lung, and also in the CNS. related publications has steadily increased over time. 1, 6 7-13 The number H4R In line, the number of known 5, 6 H4R ligands has also increased. In 2008, at the start of the studies described in this thesis, several series of H4R 1 agonists, antagonists, and inverse agonists, were reported. Interestingly, some of these ligands are selective for the H4R receptor while other ligands also have considerable 14 affinity for other histamine receptors subtypes (i.e., histamine H1, H2 and H3 receptors). For example, most imidazole-containing H4R ligands also have high affinity for the highly 14, homologous histamine H3 receptor (H3R). 15 As such, the resulting dataset is a wonderful premise to study the molecular features that are important for ligand-receptor interactions. The aim of the research described in this thesis is to understand the molecular determinants of ligands and receptors that are responsible for affinity and selectivity. Ultimately, this understanding will lead to more efficient drug discovery and hit optimization. The studies in this thesis involve computational approaches that are strongly supported by experimental data, including dedicated synthesis of interesting new ligands and their pharmacological characterization. In addition, molecular biology approaches enable site-directed mutagenesis studies to make changes on the protein level. As such, the platform allows three different levels of exploration. 1. Ligand-based studies can determine the molecular features of compounds that have affinity for the histamine receptor subtypes. Considering the availability of quality, in-house generated screening data, quantitative structure-activity studies can be undertaken. Understanding the features that are important for the ligand to bind to the receptor implies that the protein receptor site contains complementary features. This information can be used in subsequent studies. 2. Structure-based studies for GPCRs are complicated as there are not many crystal structures for GPCR solved (this situation is drastically changing only in recent months). It is therefore useful to guide and validate the homology modeling efforts by using the generated ligand-based information, as well as using 35 Chapter 2 experimental data resulting from site-directed mutagenesis and studying ligand-binding of the resulting mutant receptors. Combined, these studies should lead to detailed understanding of the interactions that are involved in ligand-H4R receptors. This understanding can be used in drug discovery approaches. 3. Virtual screening application can help to determine the accuracy and usefulness of the computational models. The use of the models in efficient and successful virtual screening campaigns can be considered as ultimate proof of understanding ligand-receptor interactions. Gratifyingly, these studies can also lead to the identification of novel hit compounds for the H4R receptor. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 36 Istyastono, E. P.; de Graaf, C.; de Esch, I. J.; Leurs, R. Molecular determinants of selective agonist and antagonist binding to the histamine H receptor. Curr. Top. Med. Chem. 2011, 11, 661-79. Leurs, R.; Chazot, P. L.; Shenton, F. C.; Lim, H. D.; de Esch, I. J. Molecular and biochemical pharmacology of the histamine H4 receptor. Br. J. Pharmacol. 2009, 157, 14-23. Lim, H. D.; Smits, R. A.; Leurs, R.; De Esch, I. J. The emerging role of the histamine H4 receptor in anti-inflammatory therapy. Curr. Top. Med. Chem. 2006, 6, 1365-73. Zampeli, E.; Tiligada, E. The role of histamine H4 receptor in immune and inflammatory disorders. Br. J. Pharmacol. 2009, 157, 24-33. Engelhardt, H.; Smits, R. A.; Leurs, R.; Haaksma, E.; de Esch, I. J. A new generation of antihistamines: Histamine H4 receptor antagonists on their way to the clinic. Curr. Opin. Drug Discov. Devel. 2009, 12, 628-43. Smits, R. A.; Leurs, R.; de Esch, I. J. Major advances in the development of histamine H4 receptor ligands. Drug Discov. Today 2009, 14, 745-53. Connelly, W. M.; Shenton, F. C.; Lethbridge, N.; Leurs, R.; Waldvogel, H. J.; Faull, R. L.; Lees, G.; Chazot, P. L. The histamine H4 receptor is functionally expressed on neurons in the mammalian CNS. Br. J. Pharmacol. 2009, 157, 55-63. Liu, C.; Ma, X.; Jiang, X.; Wilson, S. J.; Hofstra, C. L.; Blevitt, J.; Pyati, J.; Li, X.; Chai, W.; Carruthers, N.; Lovenberg, T. W. Cloning and pharmacological characterization of a fourth histamine receptor (H4) expressed in bone marrow. Mol. Pharmacol. 2001, 59, 420-6. Morse, K. L.; Behan, J.; Laz, T. M.; West, R. E., Jr.; Greenfeder, S. A.; Anthes, J. C.; Umland, S.; Wan, Y.; Hipkin, R. W.; Gonsiorek, W.; Shin, N.; Gustafson, E. L.; Qiao, X.; Wang, S.; Hedrick, J. A.; Greene, J.; Bayne, M.; Monsma, F. J., Jr. Cloning and characterization of a novel human histamine receptor. J. Pharmacol. Exp. Ther. 2001, 296, 1058-66. Nakamura, T.; Itadani, H.; Hidaka, Y.; Ohta, M.; Tanaka, K. Molecular cloning and characterization of a new human histamine receptor, HH4R. Biochem. Biophys. Res. Commun. 2000, 279, 615-20. Nguyen, T.; Shapiro, D. A.; George, S. R.; Setola, V.; Lee, D. K.; Cheng, R.; Rauser, L.; Lee, S. P.; Lynch, K. R.; Roth, B. L.; O'Dowd, B. F. Discovery of a novel member of the histamine receptor family. Mol. Pharmacol. 2001, 59, 427-33. Strakhova, M. I.; Nikkel, A. L.; Manelli, A. M.; Hsieh, G. C.; Esbenshade, T. A.; Brioni, J. D.; Bitner, R. S. Localization of histamine H4 receptors in the central nervous system of human and rat. Brain Res. 2009, 1250, 41-8. Zhu, Y.; Michalovich, D.; Wu, H.; Tan, K. B.; Dytko, G. M.; Mannan, I. J.; Boyce, R.; Alston, J.; Tierney, L. A.; Li, X.; Herrity, N. C.; Vawter, L.; Sarau, H. M.; Ames, R. S.; Davenport, C. M.; Hieble, J. P.; Wilson, S.; Bergsma, D. J.; Fitzgerald, L. R. Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol. Pharmacol. 2001, 59, 434-41. Molecular Determinants of Selective H4R Agonist and Antagonist 14. 15. Lim, H. D.; van Rijn, R. M.; Ling, P.; Bakker, R. A.; Thurmond, R. L.; Leurs, R. Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J. Pharmacol. Exp. Ther. 2005, 314, 1310-21. Lim, H. D.; Istyastono, E. P.; van de Stolpe, A.; Romeo, G.; Gobbi, S.; Schepers, M.; Lahaye, R.; Menge, W. M.; Zuiderveld, O. P.; Jongejan, A.; Smits, R. A.; Bakker, R. A.; Haaksma, E. E.; Leurs, R.; de Esch, I. J. Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies. Bioorg. Med. Chem. 2009, 17, 3987-94. 37 Chapter 2 38