Abstract |
Recent study suggests that the proinflammatory and nociceptive effects of prostaglandin E(2) are mediated by prostanoid receptor subtype EP(4) and prostanoid EP(4) receptor may be a potential target for the treatment of inflammatory pain. Here we describe pharmacological characterization of a novel prostanoid EP(4) receptor antagonist, CJ-042,794 (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl) oxy] phenyl} carbonyl) amino] ethyl} benzoic acid) in comparison with piroxicam (non-steroidal anti-inflammatory drug) or rofecoxib (cyclooxygenase-2 inhibitor). CJ-042,794 competitively antagonized cAMP accumulation with a pA(2) value of 8.7 in HEK293 cells overexpressing rat prostanoid EP(4) receptors. Orally administered CJ-042,794 dose-dependently inhibited carrageenan-induced mechanical hyperalgesia with an ED(50) value of 4.7 mg/kg (11 micromol/kg) and its maximal activity was somewhat less effective than that of 10 mg/kg piroxicam (30 micromol/kg p.o.). When CJ-042,794 and rofecoxib were administered to adjuvant-induced arthritis rats on Days 12-22 twice daily, both compounds reversed paw swelling to normal levels. These results suggest that a pharmacological blockade of the prostanoid EP(4) receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
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Authors | Akio Murase, Takako Okumura, Ayano Sakakibara, Hiroko Tonai-Kachi, Kazunari Nakao, Junji Takada |
Journal | European journal of pharmacology
(Eur J Pharmacol)
Vol. 580
Issue 1-2
Pg. 116-21
(Feb 02 2008)
ISSN: 0014-2999 [Print] Netherlands |
PMID | 18031725
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- (S)-4-(1-(5-chloro-2-(4-fluorophenyoxy) benzamido)ethyl) benzoic acid
- Analgesics
- Anti-Inflammatory Agents
- Benzamides
- Benzoates
- Lactones
- Ptger4 protein, rat
- Receptors, Prostaglandin E
- Receptors, Prostaglandin E, EP4 Subtype
- Sulfones
- rofecoxib
- Piroxicam
- Cyclic AMP
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Topics |
- Administration, Oral
- Analgesics
(administration & dosage, pharmacology)
- Animals
- Anti-Inflammatory Agents
(administration & dosage, pharmacology)
- Benzamides
- Benzoates
(administration & dosage, pharmacology)
- Cell Line
- Cyclic AMP
(metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- In Vitro Techniques
- Inflammation
(drug therapy)
- Lactones
(pharmacology)
- Male
- Pain
(drug therapy)
- Pain Measurement
- Piroxicam
(pharmacology)
- Rats
- Rats, Inbred Lew
- Receptors, Prostaglandin E
(antagonists & inhibitors)
- Receptors, Prostaglandin E, EP4 Subtype
- Sulfones
(pharmacology)
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