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 α-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.
Footnotes
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This work was supported by a grant from the National Arthritis Foundation, by the American Foundation for Pharmaceutical Education, and by the National Institutes of Health (Grant GM40540).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.110940.
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ABBREVIATIONS: CGRP, calcitonin gene-related peptide; SP, substance P; PAM, peptidylglycine α-monooxygenase; AIP, adjuvant-induced polyarthritis; PBA, 4-phenyl-3-butenoic acid; AOPHA, 5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid; AOPHA-Me, methyl ester of AOPHA; COX, cyclooxygenase; DMSO, dimethyl sulfoxide; FCA, Freund's complete adjuvant; sPLA2, secretory phospholipase A2; EIA, enzyme immunoassay.
- Received August 1, 2006.
- Accepted November 28, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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