Antagonists and Negative Allosteric Modulators - Late in the 1990's, compound 16 (CPCCOOEt) emerged as an important pharmacological tool because it was demonstrated to be a low affinity, selective non-competitive antagonist that interacted within the mGluRI receptor transmembrane domain (31,32). Over the past few years, several mGluRI antagonists of new structural classes have been identified that are unique from 16. A series of patents were published on 17 and 18, which are alpha, beta-anellated butyrolactones (33-37). It has been reported that 17, known as BAY36-7620, has shown a neuroprotective effect in animal models of cerebral infarction as well as being classified as more of an inverse agonist than 16 based on its inhibition of the mGluRI constitutive activity and stabilizing the inactive state of the transmembrane domain (38). Compound 18 is from a recent patent in which more than 500 compounds are exemplified, with this particular analog being one of nine compounds specifically claimed (39). However, no biological data were presented.

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Similarly, at about the same time, several patents were issued that encompassed benzimidazole carboxamides, such as 19, for use as neuroprotective agents, as described in a model of cerebral infarction (40,41). These compounds had reported affinities for the mGluRI receptor in the low nanomolar range as well as dose-dependent effects between 10 and 100 mg/kg po in a model of spinal nerve ligation. However, more recently, a series of novel thienopyrimidines were described as mGluRI antagonists such as 20 that had an IC5o value of 5 nM (42).

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