Synthesis and biological assays of new H 3-antagonists with imidazole and imidazoline polar groups

Abstract

New histamine H 3-receptor antagonists were synthesised and tested on rat brain membranes and on electrically stimulated guinea-pig ileum. The new compounds have a central polar group represented by a 2-alkylimidazole or a 2-thioimidazoline nucleus. The effect of the polar group basicity on the optimal length of the alkyl chain, connecting this group to a 4(5)-imidazolyl ring, was investigated. The best affinity values, obtained by displacement of [ 3H]-RAMHA from rat brain, were obtained for the 2-alkylimidazole derivatives ( 2a– f) with tetramethylene chain (p K i 8.03–8.97), having an intermediate basicity between that of the previously reported 2-thioimidazoles ( 1a– i) and that of 2-alkylthioimidazolines ( 3a– h). In contrast, a general lowering of affinity (p K i 5.90–7.63) was observed for compounds of the last series ( 3a– h), with a complex dependence on the terminal lipophilic group and chain length.