title: Triazole ligands reveal distinct molecular features that induce histamine H4 receptor affinity and subtly govern H4/H3 subtype selectivity.
abstract: The histamine H(3) (H(3)R) and H(4) (H(4)R) receptors attract considerable interest from the medicinal chemistry community. Given their relatively high homology yet widely differing therapeutic promises, ligand selectivity for the two receptors is crucial. We interrogated H(4)R/H(3)R selectivities using ligands with a [1,2,3]triazole core. Cu(I)-assisted "click chemistry" was used to assemble diverse [1,2,3]triazole compounds (6a-w and 7a-f), many containing a peripheral imidazole group. The imidazole ring posed some problems in the click chemistry putatively due to Cu(II) coordination, but Boc protection of the imidazole and removal of oxygen from the reaction mixture provided effective strategies. Pharmacological studies revealed two monosubstituted imidazoles (6h,p) with <10 nM H(4)R affinities and >10-fold H(4)R/H(3)R selectivity. Both compounds possess a cycloalkylmethyl group and appear to target a lipophilic pocket in H(4)R with high steric precision. The use of the [1,2,3]triazole scaffold is further demonstrated by the notion that simple changes in spacer length or peripheral groups can reverse the selectivity toward H(3)R. Computational evidence is provided to account for two key selectivity switches and to pinpoint a lipophilic pocket as an important handle for H(4)R over H(3)R selectivity.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Exact Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. m.wijtmans@vu.nl
authors.forename: Maikel
authors.initials: M
authors.lastname: Wijtmans
authors.forename: Chris
authors.initials: C
authors.lastname: de Graaf
authors.forename: Gerdien
authors.initials: G
authors.lastname: de Kloe
authors.forename: Enade P
authors.initials: EP
authors.lastname: Istyastono
authors.forename: Judith
authors.initials: J
authors.lastname: Smit
authors.forename: Herman
authors.initials: H
authors.lastname: Lim
authors.forename: Ratchanok
authors.initials: R
authors.lastname: Boonnak
authors.forename: Saskia
authors.initials: S
authors.lastname: Nijmeijer
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
authors.forename: Aldo
authors.initials: A
authors.lastname: Jongejan
authors.forename: Obbe
authors.initials: O
authors.lastname: Zuiderveld
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry; D057930:Click Chemistry; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D011869:Radioligand Assay; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D001386:Azides; C418607:HRH4 protein, human; D007093:Imidazoles; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D000074040:Receptors, Histamine H4; D014230:Triazoles