1. Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies.
- Author
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Lim HD, Istyastono EP, van de Stolpe A, Romeo G, Gobbi S, Schepers M, Lahaye R, Menge WM, Zuiderveld OP, Jongejan A, Smits RA, Bakker RA, Haaksma EE, Leurs R, and de Esch IJ
- Subjects
- Histamine H3 Antagonists pharmacology, Humans, Imidazoles chemistry, Ligands, Male, Molecular Structure, Protein Binding drug effects, Receptors, Histamine H4, Thiourea chemical synthesis, Thiourea chemistry, Thiourea pharmacology, Histamine H3 Antagonists chemistry, Imidazoles chemical synthesis, Imidazoles pharmacology, Quantitative Structure-Activity Relationship, Receptors, G-Protein-Coupled chemistry, Receptors, Histamine chemistry, Receptors, Histamine H3 chemistry, Thiourea analogs & derivatives
- 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.
- Published
- 2009
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