4-[(1H-imidazol-4-yl) methyl] benzamidines and benzylamidines: novel antagonists of the histamine H3 receptor.
A series of amidine substituted phenyl-, benzyl-, and phenethylimidazoles based on the known H3 agonist SK&F 91606 (4) has been synthesized and tested as ligands for the histamine H3 receptor. Insertion of a phenyl ring between the imidazole ring and the amidine moiety produces antagonists. The benzyl series was found to be the most potent and was further investigated. Compounds 9c and 18 (entries 5 and 12, Table 1) are potent ligands for the H3 receptor with K(i) values of 16 nM and 7.2 nM respectively. In vivo, both compounds were shown to be equipotent to thioperamide (2), the standard H3 antagonist.
Aslanian
R
R
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Brown
J E
JE
Shih
N Y
NY
wa Mutahi
M
M
Green
M J
MJ
She
S
S
Del Prado
M
M
West
R
R
Hey
J
J
D000818:Animals; D001550:Benzamidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D018100:Receptors, Histamine H3 / Q000187:drug effects / Q000502:physiology*
D001550:Benzamidines; D006633:Histamine Antagonists; D007093:Imidazoles; D007202:Indicators and Reagents; D008024:Ligands; D018100:Receptors, Histamine H3