The role of epigenetic regulation is in large parts connected to cancer, but 
additionally, its therapeutic claim in neurological disorders has emerged. 
Inhibition of histone H3 lysine N-methyltransferase, especially G9a, has been 
recently shown to restore candidate genes from silenced parental chromosomes in 
the imprinting disorder Prader-Willi syndrome (PWS). In addition to this 
epigenetic approach, pitolisant as G-protein coupled histamine H3 receptor (H3R) 
antagonist has demonstrated promising therapeutic effects for Prader-Willi 
syndrome. To combine these pioneering principles of drug action, we aimed to 
identify compounds that combine both activities, guided by the pharmacophore 
blueprint for both targets. However, pitolisant as selective H3R inverse agonist 
with FDA and EMA-approval did not show the required inhibition at G9a. 
Pharmacological characterization of the prominent G9a inhibitor A-366, that is 
as well an inhibitor of the epigenetic reader protein Spindlin1, revealed its 
high affinity at H3R while showing subtype selectivity among subsets of the 
histaminergic and dopaminergic receptor families. This work moves prominent G9a 
ligands forward as pharmacological tools to prove for a potentially combined, 
symptomatic and causal, therapy in PWS by bridging the gap between drug 
development for G-protein coupled receptors and G9a as an epigenetic effector in 
a multi-targeting approach.