In vitro and in vivo characterization of A-940894: a potent histamine H4 receptor antagonist with anti-inflammatory properties.
OBJECTIVE
The histamine H4 receptor is widely expressed in cells of immune origin and has been shown to play a role in a variety of inflammatory processes mediated by histamine. In this report, we describe the in vitro and in vivo anti-inflammatory properties of a potent histamine H4 receptor antagonist, A-940894 (4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine).


METHODS
We have analysed the pharmacological profile of A-940894 at mouse native, rat recombinant and human recombinant and native, histamine H4 receptors by radioligand binding, calcium mobilization, mast cell shape change, eosinophil chemotaxis assays and in the mouse model of zymosan-induced peritonitis.


RESULTS
A-940894 potently binds to both human and rat histamine H4 receptors and exhibits considerably lower affinity for the human histamine H1, H2 or H3 receptors. It potently blocked histamine-evoked calcium mobilization in the fluorometric imaging plate reader assays and inhibited histamine-induced shape change of mouse bone marrow-derived mast cells and chemotaxis of human eosinophils in vitro. In a mouse mast cell-dependent model of zymosan-induced peritonitis, A-940894 significantly blocked neutrophil influx and reduced intraperitoneal prostaglandin D2 levels. Finally, A-940894 has good pharmacokinetic properties, including half-life and oral bioavailability in rats and mice.


CONCLUSIONS
These data suggest that A-940894 is a potent and selective histamine H4 receptor antagonist with pharmacokinetic properties suitable for long-term in vivo testing and could serve as a useful tool for the further characterization of histamine H4 receptor pharmacology.
Strakhova
M I
MI
Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, Abbott Park, IL 60064, USA. marina.strakhova@abbott.com
Cuff
C A
CA
Manelli
A M
AM
Carr
T L
TL
Witte
D G
DG
Baranowski
J L
JL
Vortherms
T A
TA
Miller
T R
TR
Rundell
L
L
McPherson
M J
MJ
Adair
R M
RM
Brito
A A
AA
Bettencourt
B M
BM
Yao
B B
BB
Wetter
J M
JM
Marsh
K C
KC
Liu
H
H
Cowart
M D
MD
Brioni
J D
JD
Esbenshade
T A
TA
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D048430:Cell Shape; D002633:Chemotaxis; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000276:immunology; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011968:Receptors, Histamine / Q000096:biosynthesis / Q000235:genetics; D000074040:Receptors, Histamine H4; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D015054:Zymosan
C541311:4-piperazin-1-yl-6,7-dihydro-5H-benzo(6,7)cyclohepta(1,2-d)pyrimidin-2-ylamine; D000894:Anti-Inflammatory Agents, Non-Steroidal; C418607:HRH4 protein, human; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; D011994:Recombinant Proteins; D006632:Histamine; D015054:Zymosan; D015230:Prostaglandin D2; D002118:Calcium