Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies.
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.
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Exact Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
Herman D
HD
Lim
Enade P
EP
Istyastono
Andrea
A
van de Stolpe
Giuseppe
G
Romeo
Silvia
S
Gobbi
Marjo
M
Schepers
Roger
R
Lahaye
Wiro M B P
WM
Menge
Obbe P
OP
Zuiderveld
Aldo
A
Jongejan
Rogier A
RA
Smits
Remko A
RA
Bakker
Eric E J
EE
Haaksma
Rob
R
Leurs
Iwan J P
IJ
de Esch
D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry*; D011968:Receptors, Histamine / Q000737:chemistry*; D018100:Receptors, Histamine H3 / Q000737:chemistry*; D000074040:Receptors, Histamine H4; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C418607:HRH4 protein, human; D054828:Histamine H3 Antagonists; D007093:Imidazoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D013890:Thiourea; C086108:clobenpropit