The histamine H3 receptor (H3R) regulates the release of histamine and various other central transmitters such as acetylcholine, norepinephrine, glutamate and γ-aminobutyric acid. Therefore, the receptor plays a part in numerous neurologic processes. Consequently, H3R ligands have emerged as promising tools in neurogenetic disorders such as schizophrenia and Gilles de la Tourette syndrome (GTS), in the neurodegenerative conditions Alzheimer's disease (AD) and Parkinson's disease (PD), in autism-spectrum disorder (ASD) and the rare Prader–Willi syndrome (PWS). However, only two H3R inverse agonists have been marketed to date of which only one emanated from dedicated drug development campaigns.

Firstly, this work aimed to identify novel strategies in the molecular pharmacological characterisation of H3R ligands to elucidate their binding behaviour at the receptor. Secondly, novel H3R ligands should be discovered, without or with strategical co-activity at relevant other targets to address neurogenetic disorders following the multitargeting ligand (MTDL) concept.
A novel homogeneous fluorescence polarisation approach revealed marked affinity differences between prominent receptor ligands, although, they are usually determined as highly-potent ligands by common reference methods. This study points towards differences in target binding modes of various receptor ligands and emphasises the importance of non-traditional methods and receptor-labelling tracers in molecular pharmacology of H3R. Further studies revealed limits of the bioisosteric replacement according to the common pharmacophore blueprint for the medicinal chemistry of H3R ligands and solutions for the design of potent H3R drug candidates.

Furthermore, hit and lead compounds were discovered, but also drug candidates with co-activities at dopamine D2/D3 receptor (D2R/D3R) subtypes and enzymes involved in neurotransmitter degradation. Hit structures with combined H3R/D2R/D3R activity showed novel drug design strategies for MTDLs against schizophrenia and GTS. New lead and drug candidates with combined activity at monoamine oxidase B and cholinesterases (ChE) emerged as potential tools against PD and AD. Furthermore, this study demonstrates the applicability of H3R/ChE ligands in an in vivo model of ASD.
Finally, a novel MTDL approach to neurogenetic disorders was proposed, bridging to the recently identified involvement of the histone H3 methyltransferase G9a in AD, ASD and especially in PWS. Strategic manipulation of neurotransmitter levels, combined with the manipulation of cellular neuronal function, present multi-strategical perspectives to multifactorial disorders. Thus, combined H3R antagonists/G9a inhibitors represent a single strategy against a plethora of neurogenetic disorders.