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.
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.
Liu
Huaqing
H
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6100, USA. huaqing.liu@abbott.com
Altenbach
Robert J
RJ
Carr
Tracy L
TL
Chandran
Prasant
P
Hsieh
Gin C
GC
Lewis
La Geisha R
LG
Manelli
Arlene M
AM
Milicic
Ivan
I
Marsh
Kennan C
KC
Miller
Thomas R
TR
Strakhova
Marina I
MI
Vortherms
Timothy A
TA
Wakefield
Brian D
BD
Wetter
Jill M
JM
Witte
David G
DG
Honore
Prisca
P
Esbenshade
Timothy A
TA
Brioni
Jorge D
JD
Cowart
Marlon D
MD
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
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