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 H-3 agonist SK&F 91606 (4) has been synthesized and tested as ligands for the histamine H-3 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 I) are potent ligands for the H-3 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 H-3 antagonist. (C) 1998 Elsevier Science Ltd. All rights reserved.