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NEUROPHARMACOLOGY

Antiallodynic and Antihyperalgesic Effects of Selective Competitive GLU_K5 (GluR5) Ionotropic Glutamate Receptor Antagonists in the Capsaicin and Carrageenan Models in Rats

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana (C.K.J., A.A., A.M.O., D.B., R.M.A.S., S.I., P.L.O., H.E.S.); and Centro de Investigación Lilly, Madrid, Spain (E.D.)

GLU_K5 kainate receptor subunits are abundant in pain pathways, including dorsal root ganglia and spinothalamic neurons, as well as in the thalamus and brain stem. A growing body of evidence indicates that the GLU_K5 kainate receptor subtype plays a prominent role in pain transmission, particularly in persistent pain. In the present studies, compounds from a novel series of amino acid GLU_K5 receptor antagonists were evaluated for their effectiveness in reversing capsaicin-induced mechanical allodynia as well as carrageenan-induced thermal hyperalgesia. In vitro, the amino acid compounds were efficacious in blocking glutamate-evoked calcium flux in cells expressing GLU_K5 but not GLU_K6 or GLU_A2, homomeric receptors. Electrophysiologically, the compounds exhibited selectivity for kainate receptors in dorsal root ganglion cells relative to -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid hydrobromide and N-methyl-D-aspartate receptors in hippocampal pyramidal neurons. The amino acid compounds were poorly efficacious in the pain tests after s.c. or p.o. administration. However, compounds were highly efficacious after central intracisternal administration, and the rank order of potencies correlated with their rank order of affinities at GLU_K5 receptors determined in vitro, indicating that the lack of activity after systemic administration was due to poor oral bioavailability. To increase oral bioavailability, isobutyl or 2-ethylbutyl ester prodrugs of the parent amino acids were prepared. The prodrugs, which produced robust plasma levels of parent amino acids, were highly efficacious in the capsaicin and carrageenan tests. The present studies provide further evidence that selective Glu_K5 kainate receptor subtype antagonists can reverse allodynia and hyperalgesia, particularly in persistent pain states.

Address correspondence to: Dr. Harlan E. Shannon, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: H.Shannon{at}Lilly.Com