Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies.

Abstract Previous studies have demonstrated that clobenpropit ( N -(4-chlorobenzyl)- S -[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H 3 receptor (H 3 R) and H 4 receptor (H 4 R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H 3 R and H 4 R ligands. The compounds show moderate to high affinity for both the human H 3 R and H 4 R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H 4 R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H 3 R and H 4 R affinities.