Design, synthesis, and structure-activity relationships of novel non-imidazole histamine H(3) receptor antagonists

• Published in: Journal of medicinal chemistry Vol. 43; no. 12; pp. 2362 - 2370
• Main Authors: Linney, I D, Buck, I M, Harper, E A, Kalindjian, S B, Pether, M J, Shankley, N P, Watt, G F, Wright, P T
• Format: Journal Article
• Language: English
• Published: United States 15.06.2000
• Subjects: Animals; Binding, Competitive; Cerebral Cortex - metabolism; Dimaprit - analogs & derivatives; Dimaprit - chemical synthesis; Dimaprit - chemistry; Dimaprit - pharmacology; Drug Design; Guanidines - chemical synthesis; Guanidines - chemistry; Guanidines - metabolism; Guanidines - pharmacology; Guinea Pigs; Histamine Antagonists - chemical synthesis; Histamine Antagonists - chemistry; Histamine Antagonists - metabolism; Histamine Antagonists - pharmacology; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Ligands; Muscle Contraction - drug effects; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolidines - metabolism; Pyrrolidines - pharmacology; Radioligand Assay; Receptors, Histamine H1 - metabolism; Receptors, Histamine H2 - metabolism; Receptors, Histamine H3 - drug effects; Receptors, Histamine H3 - metabolism; Receptors, sigma - metabolism; Structure-Activity Relationship
• ISSN: 0022-2623

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 30and 31 are the most potent, selective non-imidazole histamine H(3) receptor antagonists reported in the literature to date.