Abstract
Drug discovery and development is a long trajectory involving many disciplines and stages. During the stages of hit-to-lead and lead optimization, design, synthesis, and pharmacological evaluation of molecules play important roles. During these stages, medicinal chemists often use Structure-Activity Relationships (SAR) or more recently emerging strategies, such as Structure-Kinetics Relationships (SKR) studies. In parallel, chemical biology tools as used in photopharmacology approaches are becoming available. As one of largest drug target families, G protein-coupled receptors (GPCRs) offer a wealth of opportunities to study these approaches and concepts.
In this thesis, the SKRs of various sets of designed compounds targeting H1R are explored and additional factors that can modulate binding kinetics of GPCR ligands have been found (chapter 2-5). Steric clash events in the limited space nearby the amine-binding region in the H1R binding pocket were found to be able to modulate binding kinetics in chapter 2. [3H]levocetirizine was chosen to analyse the kinetics of binding of unlabeled ligands with a much longer residence time. The hypothesized steric clash may help the dissociation of the ligands from the binding pocket and therefore shorten residence time. In chapter 3, analysis of benchmark H1R ligands led to the notion that tricyclic antagonists have a longer residence time at H1R than non-tricyclic ones. To further explore this molecular feature, twelve tailored antagonist analogs were synthesized and their kinetic profile investigated. The detailed SKR results show that cyclization of the aromatic groups of such analogues has a pronounced effect on the ligand-target RT, while the cyclisation effect of the basic amine moieties on the binding kinetics is less pronounced. In chapter 4, the kinetic profiles of ligands were explored using isosteric replacements of a carboxylic acid. While isosteric replacements have often been used in SAR studies, it will be important to know the effect of isosteric replacements in modulating binding kinetics. The binding affinities of non-acidic and acidic isosteres of carboxylic acids as well as a tailored set of sulfonyl-containing ligands were found to be similar. However, acidic isosteres tend to have higher KRI values (a reciprocal measure for rate of unbinding) than most non-acidic ones. Finally, covalent binding is an approach to modulate binding kinetics in a more defined way. In chapter 5, covalent binding to modulate binding kinetic profiles was explored through boron-containing ligands. The unique chemical properties of boron were hypothesized to affect ligand binding kinetics via reversible covalent binding with key lysine K191 residue in H1R. The obtained data on two sets of boron-containing ligand series indicate that kinetic profiles can be affected modestly by an α-aminoboronic acid, but does not suggest that covalent labeling is occurring on a second class of ligands comprising a benzaldehyde-boronic acid unit.
Next to the exploration of kinetic binding parameters of small-molecule ligands to address modulation of GPCR, photochemical modulation (photopharmacology) provides a new approach to GPCR modulation. Photocaging, i.e. protecting a ligand with a photoremovable group, has proven to be successful in obtaining optical control of ligand activity. In chapter 6, we took advantage of such a photocaging strategy on H1R. A designed coumarin-caged H1R antagonist has a 100-fold lower affinity for the human H1R. Uncaging with 400 nm light results in release of the parent compound desloratadine and an associated efficient blockade of H1R.
In summary, this thesis presents the design and synthesis of tool compounds with tailored kinetic binding profiles or photopharmacological features, that can help in the future understanding of H1R pharmacology and in the development of novel ligands.
Original language | English |
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Qualification | PhD |
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Award date | 6 Apr 2021 |
Place of Publication | s.l. |
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Publication status | Published - 6 Apr 2021 |