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NEUROPHARMACOLOGY

Systemic and Intrathecal Effects of a Novel Series of Phospholipase A₂ Inhibitors on Hyperalgesia and Spinal Prostaglandin E₂ Release

Departments of Anesthesiology (T.L.Y., C.I.S., B.F., X.-Y.H.) and Chemistry and Biochemistry (D.S., E.A.D.), School of Medicine, University of California, San Diego, La Jolla, California; Department of Chemistry, University of Athens, Athens, Greece (G.K., C.G.K.); and Department of Pharmaceutical Chemistry, University of Thessaloniki, Thessaloniki, Greece (D.H.-L.)

Phospholipase A₂ (PLA₂) forms are expressed in spinal cord, and inhibiting spinal PLA₂ 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 PLA₂ (cPLA₂) and group VIA calcium-independent PLA₂ (iPLA₂) in inhibition assays using human recombinant enzyme. The rank ordering of potency in blocking group IVA cPLA₂ 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 iPLA₂ was AX048, AX057 > AX006, and AX010. No agent altered recombinant cyclooxygenase activity. In vivo, i.t. (30 µg) and systemic (0.2-3 mg/kg i.p.) AX048 blocked carrageenan 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 prostaglandin E₂ (PGE₂) release. AX048 alone inhibited PGE₂ 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 cPLA₂, which produces a potent antihyperalgesia. The other agents, although demonstrating enzymatic activity in cell-free assays, appear unable to gain access to the intracellular PLA₂ toward which their action is targeted.

Address correspondence to: Dr. Tony L. Yaksh, Department of Anesthesiology University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818. E-mail: tyaksh{at}ucsd.edu

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