Exploratory scaffold hopping strategies led to identification of novel histamine H3 and H4 receptor ligands

Introduction Histamine H 3 and H 4 receptors (H 3 R and H 4 R) have been explored as attractive targets for the treatment of neuropsychological and inflammatory conditions, respectively, due to their expression profiles and involvement in the pathophysiological mechanisms of these conditions. Although these receptors share high structural similarity, selective ligands are frequently reported in the literature. Generally, H 3 R/H 4 R ligands share a common chemotype containing an aromatic region and a basic moiety bridged by a variable linker group. Our group has been exploring this chemotype to identify novel H 3 R/H 4 R ligands, with a particular focus on the LINS01 and LINS05 series, which showed nanomolar affinity. Methods In this work a scaffold hopping strategy was used to identify novel structural frameworks that bind to these receptors and to provide new data regarding the structure-activity relationships (SAR) of H 3 R/H 4 R ligands. Two sets of compounds were designed from known H 3 R/H 4 R prototypes using ring opening, homologation and bioisosterism strategies; these compounds were synthesized and assessed for their affinity at H 3 R/H 4 R. Results The LINS05 set led to identification of compounds with micromolar to submicromolar affinity toward H 3 R and selectivity over H 4 R, among which compound 7 (pKi 6.27) was the most potent. The compounds from LINS01 set mostly showed nanomolar affinities to H 3 R, with compound 11 being the most potent and selective toward H 3 R (pKi 7.02), while compound 14 was the most potent for H 4 R (pKi H 4 R 5.23; H 3 R 6.27). Docking experiments were carried out to analyze the potential interactions that these compounds may perform with the receptors and to rationalize the role of each structural modifications on the binding affinities. Conclusion In summary, the results added important SAR data to the H 3 R/H 4 R field, and novel prototypes were identified for further optimization.