GLUR5 Antagonists as Novel Migraine Therapies Johnson KW, Dieckman DK, Phebus LA, et al. Cephalalgia 2001;21:268 BACKGROUND: L-glutamate activates neurons in the trigeminal nucleus caudalis (TNC). Furthermore, non-NMDA ionotropic glutamate receptors such as GluR5 are expressed in rat trigeminal ganglion (TG), and GluR5 receptors play an important role in central sensitization (CS). CS is implicated in, and the trigeminal system is at the core of, migraine. Therefore, we hypothesized that GluR5 receptor antagonists would be effective in preclinical models of migraine. OBJECTIVES: 1) To test the potency and efficacy of GluR5 antagonists with varying degrees of affinity and selectivity for the GluR5/kainate receptor in the dural plasma protein extravasation (PPE) and the c-fos models of migraine. 2) To test these GluR5 receptor antagonists for their ability to contract the rabbit saphenous vein (RSV) in vitro. METHODS: GluR5 antagonists were synthesized in the Lilly Research Laboratories. Ligand binding studies using recombinant human non-NMDA receptors expressed in HEK293 cell membranes were used to determine compound affinity. We evaluated parenterally administered compounds in the PPE and the c-fos models induced by electrical stimulation of male rats TG. Fos protein in the TNC was measured in the c-fos experiment. Ring preparations of RSV were suspended in tissue baths and isometric contractions were recorded following incremental increases in the concentration of the test compound. Sumatriptan was used as a positive control for the RSV studies. RESULTS: LY293558, LY382884 and LY435735 dose-dependently blocked protein extravasation in the PPE model. The rank order of potency correlated with affinity for GluR5. In contrast, LY300168, a potent and selective AMPA antagonist, did not block protein extravasation, even at relatively high doses. LY293558 and LY435735 also blocked c-fos expression in the TNC. LY293558 and LY382884 did not contract the tissue in the RSV assay at concentrations up to 100 mM. CONCLUSIONS: The inhibitory effects of GluR5 antagonists in the PPE and c-fos preclinical models of migraine suggest a novel role for GluR5 antagonism in migraine therapy. The lack of efficacy of the selective AMPA antagonist LY300168 in PPE does not support a role for this mechanism in migraine. The lack of activity of these compounds in the RSV provides a therapeutic advantage of GluR5 antagonists over current vasoactive migraine therapies. These pharmacological properties of GluR5 antagonists suggest that they could be used in the treatment of acute migraine without a cardiovascular liability.