HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Anti-inflammatory effects of 4-phenyl-3-butenoic acid and 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester, potential inhibitors of neuropeptide bioactivation.

Abstract
Substance P (SP) and calcitonin gene-related peptide (CGRP) are well established mediators of inflammation. Therefore, inhibition of the biosynthesis of these neuropeptides is an attractive potential strategy for pharmacological intervention against a number of inflammatory diseases. The final step in the biosynthesis of SP and CGRP is the conversion of their glycine-extended precursors to the active amidated peptide, and this process is catalyzed by sequential action of the enzymes peptidylglycine alpha-monooxygenase (PAM) and peptidylamidoglycolate lyase. We have demonstrated previously that 4-phenyl-3-butenoic acid (PBA) is a PAM inhibitor, and we have also shown that in vivo inhibition of serum PAM by PBA correlates with this compound's ability to inhibit carrageenan-induced edema in the rat. Here we demonstrate the ability of PBA to inhibit all three phases of adjuvant-induced polyarthritis (AIP) in rats; this represents the first time that an amidation inhibitor has been shown to be active in a model of chronic inflammation. We recently introduced 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid (AOPHA) as one of a new series of mechanism-based amidation inhibitors. We now report for the first time that AOPHA and its methyl ester (AOPHA-Me) are active inhibitors of serum PAM in vivo, and we show that AOPHA-Me correspondingly inhibits carrageenan-induced edema in rats in a dose-dependent manner. Neither PBA nor AOPHA-Me exhibits significant cyclooxygenase (COX) inhibition in vitro; thus, the anti-inflammatory activities of PBA and AOPHA-Me are apparently not a consequence of COX inhibition. We discuss possible pharmacological mechanisms that may account for the activities of these new anti-inflammatory compounds.
AuthorsJohn D Bauer, Jeffrey A Sunman, Michael S Foster, Jeremy R Thompson, Alison A Ogonowski, Stephen J Cutler, Sheldon W May, Stanley H Pollock
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 320 Issue 3 Pg. 1171-7 (Mar 2007) ISSN: 0022-3565 [Print] United States
PMID17138865 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester
  • Adjuvants, Immunologic
  • Anti-Inflammatory Agents, Non-Steroidal
  • Caproates
  • Esters
  • Fatty Acids, Monounsaturated
  • Neuropeptides
  • 4-phenyl-3-butenoic acid
  • Substance P
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Phospholipases A
  • Group II Phospholipases A2
Topics
  • Adjuvants, Immunologic
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology, therapeutic use)
  • Arthritis, Experimental (drug therapy, metabolism)
  • Caproates (chemistry, pharmacology, therapeutic use)
  • Cyclooxygenase 1 (blood, metabolism)
  • Cyclooxygenase 2 (blood, metabolism)
  • Dose-Response Relationship, Drug
  • Edema (drug therapy, metabolism)
  • Esters (chemistry, pharmacology, therapeutic use)
  • Fatty Acids, Monounsaturated (chemistry, pharmacology, therapeutic use)
  • Group II Phospholipases A2
  • Humans
  • In Vitro Techniques
  • Male
  • Molecular Structure
  • Neuropeptides (metabolism)
  • Phospholipases A (metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Sciatic Nerve (metabolism)
  • Substance P (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: