Design, synthesis, and structure-activity relationships of novel non-imidazole histamine H3 receptor antagonists

Novel, potent, and selective non-imidazole histamine H-3 receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H-3 receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H-1 and H-2, receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30 and 31 are the most potent, selective non-imidazole histamine Ha receptor antagonists reported in the literature to date.