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.
Lim
Herman D
HD
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.
Istyastono
Enade P
EP
van de Stolpe
Andrea
A
Romeo
Giuseppe
G
Gobbi
Silvia
S
Schepers
Marjo
M
Lahaye
Roger
R
Menge
Wiro M B P
WM
Zuiderveld
Obbe P
OP
Jongejan
Aldo
A
Smits
Rogier A
RA
Bakker
Remko A
RA
Haaksma
Eric E J
EE
Leurs
Rob
R
de Esch
Iwan J P
IJ
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