title: Design, synthesis, and structure-activity relationships of novel non-imidazole histamine H(3) receptor antagonists.
abstract: 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.
authors.affiliation: The James Black Foundation, 68 Half Moon Lane, Dulwich, London SE24 9JE, U.K. ian.linney@kcl.ac.uk
authors.forename: I D
authors.initials: ID
authors.lastname: Linney
authors.forename: I M
authors.initials: IM
authors.lastname: Buck
authors.forename: E A
authors.initials: EA
authors.lastname: Harper
authors.forename: S B
authors.initials: SB
authors.lastname: Kalindjian
authors.forename: M J
authors.initials: MJ
authors.lastname: Pether
authors.forename: N P
authors.initials: NP
authors.lastname: Shankley
authors.forename: G F
authors.initials: GF
authors.lastname: Watt
authors.forename: P T
authors.initials: PT
authors.lastname: Wright
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D017259:Dimaprit / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008024:Ligands; D009119:Muscle Contraction / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D017480:Receptors, sigma / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D006146:Guanidines; D006633:Histamine Antagonists; D008024:Ligands; C410935:N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine; C410934:N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine; D011759:Pyrrolidines; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; D017480:Receptors, sigma; C101491:sigma1-binding protein, rat; D017259:Dimaprit