title: Agonist/antagonist modulation in a series of 2-aryl benzimidazole H4 receptor ligands.
abstract: The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development, L.L.C, 3210 Merryfield Row, San Diego, CA 92121, USA. bsavall@its.jnj.com
authors.forename: Brad M
authors.initials: BM
authors.lastname: Savall
authors.forename: James P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Venable
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Buzard
authors.forename: Robin
authors.initials: R
authors.lastname: Thurmond
authors.forename: Michael
authors.initials: M
authors.lastname: Hack
authors.forename: Patricia
authors.initials: P
authors.lastname: McGovern
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D017442:Histamine Agonists / Q000737:chemistry / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects* / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; C418607:HRH4 protein, human; D017442:Histamine Agonists; D006633:Histamine Antagonists; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4