Combination of prototypical histamine H 3 and H 4 receptor pharmacophores

Abstract

The human histamine H 3 and H 4 receptor subtypes (hH 3 R, hH 4 R) are structurally highly related G protein-coupled receptors. Preclinical and clinical data hint at an involvement of the two receptors in diseases like itch and pain. According to the structural requirements responsible for affinity and selectivity for both receptor subtypes, we investigated the combination of 2-aminopyrimidines and related structures (for H 4 R) with the well-established and robust (3- piperidinopropoxy)phenyl pharmacophore (for H 3 R). In an effort to design new structurally hybrid compounds, a novel series of substituted pyrimidines were synthesized. The compounds were prepared by microwave-assisted aromatic nucleophilic substitution reactions of either 2-amino-4,5-dichloropyrimidine or 2,4-dichloropyrimidine. The in vitro receptor binding properties were obtained by radioligand displacement assay on HEK-293 cells stably expressing the hH 3 R and on Sf9 cells transiently expressing the hH 4 R (co-expressed with Gai2 and Gb1c2 subunits). Slight structural changes of the hH 4 R scaffold evoked severe changes in hH 4 R affinity, although the 2,4-diaminopyrimidine scaffold can be found in many potent hH 4 R ligands. In contrast, hH 3 R affinity has barely been affected by introducing the pyrimidine-related motif on the H 3 R pharmacophore. Novel compounds with hH 3 R binding properties in the nanomolar concentration range have been achieved.