RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Bauer, JD  Sunman, JA  Foster, MS  Thompson, JR  Ogonowski, AA  Cutler, SJ  May, SW  Pollock, SH 
Citation: Bauer JD, etal., J Pharmacol Exp Ther. 2007 Mar;320(3):1171-7. Epub 2006 Nov 30.
RGD ID: 6483527
Pubmed: PMID:17138865   (View Abstract at PubMed)
DOI: DOI:10.1124/jpet.106.110940   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
PAMHumanExperimental Arthritis  ISOPam (Rattus norvegicus) RGD 
PamRatExperimental Arthritis  IDA  RGD 
PamMouseExperimental Arthritis  ISOPam (Rattus norvegicus) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Pam  (peptidylglycine alpha-amidating monooxygenase)

Genes (Mus musculus)
Pam  (peptidylglycine alpha-amidating monooxygenase)

Genes (Homo sapiens)
PAM  (peptidylglycine alpha-amidating monooxygenase)


Additional Information