Design, Synthesis, and Structure−Activity Relationships of Novel Non-Imidazole Histamine H3 Receptor Antagonists

Novel, potent, and selective non-imidazole histamine H3 receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pKI 7.32 ± 0.12, pKB 5.93 ± 0.17). Detailed structure−activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pKI 8.38 ± 0.21, pKB 8.39 ± 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pKI 8.78 ± 0.12, pKB 8.38 ± 0.10), 31, exhibit high affinity for the histamine H3 receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H1 and H2, receptor subtypes and a 100-fold selectivity in the σ1 binding assay. Compounds 30 and 31 are the most potent, selective non-imidazole histamine H3 receptor antagonists reported in the literature to date.