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
alpha-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-ethyl-butyl
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.