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Influence of imidazole replacement in different structural classes of histamine H3-receptor antagonists

2001; Elsevier BV; Volume: 13; Issue: 3 Linguagem: Inglês

10.1016/s0928-0987(01)00106-3

1879-0720

Galina Meier, Joachim Apelt, Ulrich Reichert, Sven Graßmann, Xavier Ligneau, Sigurd Elz, Fabien Leurquin, C. Robin Ganellin, Jean‐Charles Schwartz, Walter Schunack, Holger Stark,

Polyamine Metabolism and Applications

The reference compounds for histamine H3-receptor antagonists carry as a common feature an imidazole moiety substituted in the 4-position. Very recently novel ligands lacking an imidazole ring have been described possessing a N-containing non-aromatic heterocycle instead. In this study we investigated whether imidazole replacement, favourably by a piperidine moiety, is generally applicable to different structural classes of reference compounds, e.g., thioperamide, carboperamide, clobenpropit, FUB 181, ciproxifan, etc. While replacement led to a loss of affinity for many of the compounds, it was successfully applied to some ether derivatives. The piperidine analogues of FUB 181 and ciproxifan, 3-(4-chlorophenyl)propyl 3-piperidinopropyl ether hydrogen oxalate (6) and cyclopropyl 4-(3-piperidinopropyloxy)phenyl methanone hydrogen maleate (7), almost maintained in vitro affinities, pKi values of 7.8 and 8.4, respectively, and showed high potency in vivo after p.o. administration (ED50 values of 1.6 and 0.18 mg/kg, respectively).