RESEARCH HIGHLIGHTS

URLsHIGHLIGHT ADVISORS ERIK DE CLERCQ ANALGESICS KATHOLIEKE UNIVERSITEIT LEUVEN, BELGIUM RODERICK FLOWER New clues in the WILLIAM HARVEY RESEARCH INSTITUTE, QMW, LONDON, UK YOSHIJI FUJITA acetaminophen mystery CLINICAL PROTEOME CENTER, TOKYO MEDICAL UNIVERSITY Although acetaminophen (para- was this path of investigation that was F. PETER GUENGERICH cetamol) has been used clinically followed by Zygmunt and colleagues. VANDERBILT UNIVERSITY NASHVILLE, TN, USA for more than a century, its mode The stimulus for their studies was of action is still not clear. Writing in the striking relationship between the FRANZ HEFTI the Journal of Biological Chemistry, structures of acetaminophen and the RINAT NEUROSCIENCE CORPORATION, PALO ALTO, Zygmunt and colleagues have now N-acyl phenolamine AM404, which CA, USA provided evidence for a new and is both a potent activator of the ion

JOAN HELLER BROWN unexpected mechanism through channel TRPV1 and has effects on UNIVERSITY OF CALIFORNIA which acetaminophen could exert cannabinoid CB1 receptors. Both SAN DIEGO, CA, USA its analgesic effects. TRPV1 and CB1 receptors are involved MADS KROGSGAARD Acetaminophen differs signifi- in pain and thermoregulatory path- THOMSEN cantly from aspirin and other non- ways and are viewed as promising synthesize AM404 from p-aminophe- NOVO NORDISK, BAGSVAERD, steroidal anti-inflammatory drugs targets for the treatment of pain and nol and arachidonic acid in vitro. In DENMARK (NSAIDs), with which it is often inflammation. addition, no formation of AM404 was HUGO KUBINYI grouped because of their shared anal- The structural relationship observed in vitro or in vivo in brain UNIVERSITY OF HEIDELBERG, gesic and antipyretic effects, as it is between AM404 and acetaminophen tissue from mice that lacked FAAH. GERMANY only a weak anti-inflammatory agent suggested that following deacety- Finally, the authors also showed ROBERT LANGER and has a low incidence of gastric side lation to its metabolite p-ami- that AM404 inhibits purified COX1 MASSACHUSETTS INSTITUTE effects. The effects of NSAIDs are nophenol, acetaminophen could be and COX2 and prostaglandin forma- OF TECHNOLOGY CAMBRIDGE, MA, USA thought to depend on their ability to conjugated with arachidonic acid to tion in lipopolysaccharide-stimulated inhibit two forms of cyclooxygenase, give AM404. The authors provided macrophages. In summary, the JULIO LICINIO COX1 and COX2, and the conse- several lines of evidence to support identification of AM404 as a novel UNIVERSITY OF CALIFORNIA LOS ANGELES, CA, USA quent inhibition of the synthesis of this idea, including demonstrating metabolite of acetaminophen in the prostaglandins. However, despite that deuterium-labelled AM404 and nervous system that affects several CHRISTOPHER LIPINSKI PFIZER GLOBAL RESEARCH much research, definitive proof that p-aminophenol were dose-depend- important targets involved in pain AND DEVELOPMENT, GROTON, the analgesic and antipyretic effects ently formed in rat brain after the and thermoregulatory pathways pro- CT, USA of acetaminophen are dependent on administration of deuterium-labelled vides a new hypothesis for explain- TOMI SAWYER COX is still lacking. Indeed, inhibi- acetaminophen at doses that produce ing the acetaminophen mystery. The ARIAD PHARMACEUTICALS, tion of a third form of COX, COX3, is analgesia in rodents. AM404 could confirmation of the relevance of this CAMBRIDGE, MA, USA one of the more recent proposals that also be detected in the spinal cord hypothesis to the pharmacological JANET WOODCOCK has been put forward to explain the of rats given acetaminophen and effects of acetaminophen in humans FOOD & DRUG unusual effects of acetaminophen, p-aminophenol. will surely be eagerly anticipated. ADMINISTRATION, ROCKVILLE, but further analysis has suggested Furthermore, the authors provide Peter Kirkpatrick MD, USA that this interaction is unlikely to be evidence for the pathway by which clinically relevant. AM404 is formed, by showing that References and links ORIGINAL RESEARCH PAPER Hogestatt, E. There have also been indications fatty acid amide hydrolase (FAAH), et al. Conversion of acetaminophen to the that the analgesic effects of acetamin- which is known to hydrolyse endog- bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid ophen are mediated by molecular enous compounds related to AM404, conjugation in the nervous system. J. Biol. Chem. targets distinct from COX, and it can act in the reverse direction, and 280, 31405–31412 (2005)

NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | NOVEMBER 2005 | 883