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

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

Bioorganic & medicinal chemistry (2009-05-06)

Herman D Lim, Enade P Istyastono, Andrea van de Stolpe, Giuseppe Romeo, Silvia Gobbi, Marjo Schepers, Roger Lahaye, Wiro M B P Menge, Obbe P Zuiderveld, Aldo Jongejan, Rogier A Smits, Remko A Bakker, Eric E J Haaksma, Rob Leurs, Iwan J P de Esch

PMID19414267

摘要

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.