New high affinity H3 receptor agonists without a basic side chain.
In this study, we replaced the basic amine function of the known histamine H(3) receptor agonists imbutamine or immepip with non-basic alcohol or hydrocarbon moieties. All compounds in this study show a moderate to high affinity for the cloned human H(3) receptor and, unexpectedly, almost all of them act as potent agonists. Moreover, in the alcohol series, we consistently observed an increased selectivity for the human H(3) receptor over the human H(4) receptor, but none of the compounds in this series possess increased affinity and functional activity compared to their alkylamine congeners. In this new series of compounds VUF5657, 5-(1H-imidazol-4-yl)-pentan-1-ol, is the most potent histamine H(3) receptor agonist (pK(i) = 8.0 and pEC(50) = 8.1) with a 320-fold selectivity at the human H(3) receptor over the human H(4) receptor.
Kitbunnadaj
Ruengwit
R
Leiden/Amsterdam Center of Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit Amsterdam, The Netherlands.
Hoffmann
Marcel
M
Fratantoni
Silvina A
SA
Bongers
Gerold
G
Bakker
Remko A
RA
Wieland
Kerstin
K
el Jilali
Ahmed
A
De Esch
Iwan J P
IJ
Menge
Wiro M P B
WM
Timmerman
Henk
H
Leurs
Rob
R
D045744:Cell Line, Tumor; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D017442:Histamine Agonists; D011968:Receptors, Histamine