title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Mercer University College of Pharmacy and Health Sciences, Atlanta, GA 30341, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Bauer
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sunman
authors.forename: Michael S
authors.initials: MS
authors.lastname: Foster
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Thompson
authors.forename: Alison A
authors.initials: AA
authors.lastname: Ogonowski
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Cutler
authors.forename: Sheldon W
authors.initials: SW
authors.lastname: May
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Pollock
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D002208:Caproates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051545:Cyclooxygenase 1 / Q000097:blood / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy* / Q000378:metabolism; D004952:Esters / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D054501:Group II Phospholipases A2; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009479:Neuropeptides / Q000378:metabolism*; D010741:Phospholipases A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000378:metabolism; D013373:Substance P / Q000378:metabolism
chemical_list: C518642:5-(acetylamino)-4-oxo-6-phenyl-2-hexenoic acid methyl ester; D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002208:Caproates; D004952:Esters; D005229:Fatty Acids, Monounsaturated; D009479:Neuropeptides; C064180:4-phenyl-3-butenoic acid; D013373:Substance P; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D010741:Phospholipases A; D054501:Group II Phospholipases A2