title: cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain responses against carrageenan-induced hyperalgesia.
abstract: cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine, 4 (A-987306) is a new histamine H(4) antagonist. The compound is potent in H(4) receptor binding assays (rat H(4), K(i) = 3.4 nM, human H(4) K(i) = 5.8 nM) and demonstrated potent functional antagonism in vitro at human, rat, and mouse H(4) receptors in cell-based FLIPR assays. Compound 4 also demonstrated H(4) antagonism in vivo in mice, blocking H(4)-agonist induced scratch responses, and showed anti-inflammatory activity in mice in a peritonitis model. Most interesting was the high potency and efficacy of this compound in blocking pain responses, where it showed an ED(50) of 42 mumol/kg (ip) in a rat post-carrageenan thermal hyperalgesia model of inflammatory pain.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. huaqing.liu@abbott.com
authors.forename: Huaqing
authors.initials: H
authors.lastname: Liu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Altenbach
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Carr
authors.forename: Prasant
authors.initials: P
authors.lastname: Chandran
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.forename: La Geisha R
authors.initials: LG
authors.lastname: Lewis
authors.forename: Arlene M
authors.initials: AM
authors.lastname: Manelli
authors.forename: Ivan
authors.initials: I
authors.lastname: Milicic
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Marina I
authors.initials: MI
authors.lastname: Strakhova
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vortherms
authors.forename: Brian D
authors.initials: BD
authors.lastname: Wakefield
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Brioni
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002351:Carrageenan; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy*; D008024:Ligands; D051379:Mice; D015394:Molecular Structure; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control*; D010538:Peritonitis / Q000188:drug therapy; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C539548:4-(piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro(2,3-h)quinazolin-2-amine; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001572:Benzofurans; C418607:HRH4 protein, human; C498829:Hrh4 protein, mouse; C498828:Hrh4 protein, rat; D008024:Ligands; D011799:Quinazolines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D002351:Carrageenan