Antiinflammatory and analgesic activity of an inhibitor of neuropeptide amidation.
4-Phenyl-3-butenoic acid (PBA) has been shown in vitro to be a turnover-dependent inactivator of peptidylglycine alpha-monooxygenase (PAM), the rate-limiting enzyme involved in the formation of amidated neuropeptides from their glycine-extended precursors. In the studies reported herein, we have shown that PBA produces a dose-dependent (50-500 mg/kg s.c.) inhibition of serum PAM activity in normal rats without affecting peptidylamidoglycolate lyase activity. Because amidated neuropeptides such as substance P and calcitonin gene-related peptide are involved in acute inflammation, we evaluated the effects of PBA on carrageenan-induced inflammation in rats. The acute administration of PBA (s.c. or i.p.) produced a dose-related inhibition of edema with maximum inhibition (67%) observed at 2 hr postphlogistic agent. In addition, the continuous administration of PBA to animals over a 7-day period using osmotic pumps not only inhibited hind paw swelling induced by carrageenan but also inhibited serum PAM activity and reduced tissue levels of substance P in hind paws. These results demonstrate for the first time a correlation between the antiinflammatory activity produced by an inhibitor of peptide amidation with its ability to inhibit serum PAM activity and lower endogenous tissue levels of substance P. Moreover, these results confirm our contention that PAM is an excellent pharmacological target for controlling the acute inflammatory response. We also demonstrate the ability of PBA to inhibit phenyl-p-quinone and acetylcholine-induced writhing in mice without affecting the spinally mediated tail immersion assay in rats. Because this analgesic effect was extremely rapid (within 15 min), PBA may be producing this effect by a mechanism other than peptide amidation.
Ogonowski
A A
AA
School of Pharmacy, Mercer University, Atlanta, Georgia 30341, USA.
May
S W
SW
Moore
A B
AB
Barrett
L T
LT
O'Bryant
C L
CL
Pollock
S H
SH
D019760:Amidine-Lyases; D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001920:Bradykinin; D002351:Carrageenan; D004487:Edema; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D007700:Kinetics; D008190:Lyases / Q000378:metabolism; D008297:Male; D051379:Mice; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009097:Multienzyme Complexes; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin; D013373:Substance P / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005229:Fatty Acids, Monounsaturated; D009097:Multienzyme Complexes; C064180:4-phenyl-3-butenoic acid; D012701:Serotonin; D013373:Substance P; D002351:Carrageenan; D006899:Mixed Function Oxygenases; C035189:peptidylglycine monooxygenase; D008190:Lyases; D019760:Amidine-Lyases; C068521:peptidylamidoglycolate lyase; D001920:Bradykinin