| Autor: |
Bauer JD; Department of Pharmaceutical Sciences, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA 30341, USA., Sunman JA, Foster MS, Thompson JR, Ogonowski AA, Cutler SJ, May SW, Pollock SH |
| Jazyk: |
angličtina |
| Zdroj: |
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2007 Mar; Vol. 320 (3), pp. 1171-7. Date of Electronic Publication: 2006 Nov 30. |
| DOI: |
10.1124/jpet.106.110940 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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