Systemic and Intrathecal Effects of a Novel Series of Phospholipase A_2 Inhibitors on Hyperalgesia and Spinal Prostaglandin E_2 Release

摘要

Phospholipase A_2(PLA_2)forms are expressed in spinal cord,and inhibiting spinal PLA_2 induces a potent antihyperalgesia.Here,we examined the antihyperalgesic effects after systemic and i.t.delivery of four compounds constructed with a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four-carbon tether.These molecules were characterized for their ability to block group IVA calcium-dependent PLA_2(cPLA_2)and group VIA calcium-independent PLA_2(iPLA_2)in inhibition assays using human recombinant enzyme.The rank ordering of potency in blocking group IVA cPLA_2 was AX048(ethyl 4-[(2-oxohexadecanoyl)amino]butanoate),AX006(4-[(2-oxohexadecanoyl)amino]butanoic acid),and AX057(tert-butyl 4-[(2-oxohexadecanoyl)amino]butanoate)> AX010(methyl 4-[(2-oxohexadecanoyl)amino]butanoate)and for inhibiting group VIA iPLA_2 was AX048,AX057 > AX006,and AX010.No agent altered recombinant cyclooxygenase activity.In vivo,i.t.(30 mug)and systemic(0.2-3 mg/kg i.p.)AX048 blocked carra-geenan hyperalgesia and after systemic delivery in a model of spinally mediated hyperalgesia induced by i.t.substance P(SP).The other agents were without activity.In rats prepared with lumbar i.t.loop dialysis catheters,SP evoked spinal pros-taglandin E_2(PGE_2)release.AX048 alone inhibited PGE_2 release.Intrathecal SR141617,a cannabinoid CB1 inhibitor at doses that blocked the effects of i.t.anandamide had no effect upon i.t.AX048.These results suggest that AX048 is the first systemically bioavailable compound with a significant affinity for group IVA cPLA_2,which produces a potent antihyperalgesia.The other agents,although demonstrating enzymatic activity in cell-free assays,appear unable to gain access to the intracellular PLA_2 toward which their action is targeted.