Abstracts Category : Other

Synthesis and pharmacological characterization of homo- and hetero-dimeric compounds, targeting the hHR and/or hHR

by Jianfei Wan

G-protein coupled receptors are the most important class of biological targets for drug development. Among them, the histamine receptors may be considered as representative examples for aminergic GPCRs. The latest member of the histamine receptor family, the H4R, was reported to be involved in immunological processes and inflammatory diseases. However, the (patho)physiological role of the H4R is far from being fully understood. Thus, potent and selective pharmacological tools in various forms targeting H4R are required. Based on complementary and overlapping functions of hH1R and hH4R, it is presumed that combined H1R/H4R antagonism might be superior to monotherapy in the treatment of allergic diseases. In the first part of this thesis, twenty-two novel homo-dimeric ligands based on the prominent H1R antagonists diphenhydramine (3.1), pyrilamine (3.2) and dual H1R/H4R antagonist quinazoline derivative (3.3), were synthesized to probe putative accessory binding sites on hH1R and hH4R. Furthermore, their binding affinities were determined at the hH1R and/or hH4R. Between the two types of spacers which were employed in this study, connecting chains comprising amide groups exhibited similar affinity compared to their monomeric counterparts. By contrast, alkyl chains without amides showed decreased affinity at the hH1R, suggesting that the lipophilicity of the compounds plays an important role in binding affinity, e.g., high lipophilicity may result a poor solubility and high non-specific binding of the compound in assays. Since the variation of the spacer length had no significant influence on binding affinities, it may be suggested that one pharmacophore of the homo-dimeric ligand was not binding to the hH1R, thus it did not contribute to receptor-ligand binding. At the hH4R, all bivalent quinazoline-type ligands showed no obvious activity. This may be interpreted that the quinazoline-type homo-dimeric ligands are not tolerated at the hH4R. In a word, the data of the present study were not sufficient to prove the existence of accessory binding sites on hH1R and hH4R.The second part of this thesis was focused on developing dual hH1R/hH4R antagonists. Thirty benzimidazole- and quinazoline-type compounds were synthesized and pharmacologically characterized at the four human histamine receptor subtypes. The incorporation of an imidazole moiety, separated from the benzimidazole moiety by an appropriate linker, largely improved the binding affinities at the hH4R and resulted in a balanced dual hH1R/hH4R antagonist (compound 4.35b) with Ki values in the two-digit nM range. However, ligands comprising imidazolylalkyl moieties did not discriminate between hH3R and hH4R.In summary, although the dimeric approach may be an interesting and useful strategy in developing bitopic and dual target ligands targeting H1R and/or H4R, there are numerous problems associated with this approach. Due to the low homology between ligand binding sites of H1R and H4R, it appears extremely difficult to identify a common H1R/H4R pharmacophore atAdvisors/Committee Members: Straer, Andrea (advisor), Buschauer, Armin (advisor).