4-(omega-(alkyloxy)alkyl)-1H-imidazole derivatives as histamine H(3) receptor antagonists/agonists.
In an effort to develop new histamine H(3) receptor antagonists usable as pharmacological tools we present here novel unsymmetrical ether derivatives. Etherification of different omega-(1H-imidazol-4-yl)alkyl scaffolds led to compounds containing alkyl chains of increasing lengths either with or without unsaturated termini, cycloalkyl or arylalkyl moieties, or additional heteroatoms. When investigated in an in vitro assay on rat synaptosomes, the majority of compounds displayed potencies in the low nanomolar concentration range at the H(3) receptor, e.g., 4-(3-(3-cyclopentylpropyloxy)propyl)-1H-imidazole (27, K(i) = 7 nM). FUB 465, 4-(3-(ethoxy)propyl)-1H-imidazole (14), a useful tool for the characterization of constitutive activity of H(3) receptors in vivo in rodents, proved to be of high oral in vivo potency in mice (ED(50) = 0.26 mg/kg). Further, the influence of chosen compounds on specific [(35)S]GTPgammaS binding was assayed on HEK293 cell membranes expressing the human histamine H(3) receptor revealing partial agonism of the compounds in this particular model. These distinct responses are further hints for "protean agonism" in this class of compounds. Additionally, selected compounds were functionally investigated in vitro on isolated organs of the guinea-pig at H(3), H(1), and H(2) receptors.
Meier
Galina
G
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
Krause
Michael
M
Hüls
Annette
A
Ligneau
Xavier
X
Pertz
Heinz H
HH
Arrang
Jean-Michel
JM
Ganellin
C Robin
CR
Schwartz
Jean-Charles
JC
Schunack
Walter
W
Stark
Holger
H
D000818:Animals; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D018100:Receptors, Histamine H3; D016244:Guanosine 5'-O-(3-Thiotriphosphate)