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.
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Authors | John D Bauer, Jeffrey A Sunman, Michael S Foster, Jeremy R Thompson, Alison A Ogonowski, Stephen J Cutler, Sheldon W May, Stanley H Pollock |
Journal | The 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 |
PMID | 17138865
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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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
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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)
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