Research at Guilford has focused on the potential utility of GCP II inhibitors wherein excess glutamate neurotransmission has been implicated. 2-(Phosphonomethyl) pentanedioic acid (2-PMPA) is a potent, competitive GCP II inhibitor with a Ki value of 0.2 nM15; 16 (Fig 2). It exhibits a fast association rate and a slow dissociation rate. The high potency of 2-PMPA can be attributed to the strong chelation of the phosphonate group to an active site zinc atom as well as the interaction of the glutamate moiety (pentanedioic) portion of the inhibitor with the glutamate recognition site of GCPII.18 2-PMPA seems to be quite specific for GCP II, i.e., no significant activities were observed at 10 |j.M (more than 10,000-fold higher than the Ki for NAALADase inhibition) in over 100 different receptor and enzyme assays, including glutamate receptors and
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