The selective positive allosteric modulators 2, 3 and 4 of mGluRI receptors consist of tetrazole analogs, sulfonylpyrrolldines, and carbonylamino derivatives, respectively. A recent publication describes the effects of these compounds in recombinant and native mGluRI receptor functional models (22). It was reported that 2 had an EC5o value of 0.045 nM and 4 and related analogs had ECso's ranging between 1.0 and 17.0 nM. An IC50 of 0.56 nM was reported for compound 3. Until recently, no compounds have been claimed specifically as mGluR5 receptor enhancers. In 2001, it was reported that (9H-xanthene-9-carbonyl)-carbamic acid butyl ester (5), a positive allosteric modulator, potentiated an mGluR5 agonist-stimulated functional response but to a lesser degree than at the mGluRI receptor (22). This indicated that positive mGluR5 allosteric modulators were theoretically possible. Consequently, compounds 6 (DFB) and 7 (CPPHA) were recently presented as the first true examples of mGluR5 allosteric modulators (23,24).
Over the past several years, Group II agonists have been highly illustrated in the literature (6). Recent claims include compounds that behave as positive allosteric potentiators of mGluR2 and mGluR3 receptors. These compounds are disclosed as prodrugs of a bicyclo-[3.1.0]-hexane derivative 8 (LY354740) and show improved oral potency. In studies that were done in the rat fear potentiated startle model, prodrugs 9 and 10 achieved plasmas levels at least 15 times higher in the pro-drug dosed animals than those receiving only 8 at doses of 5 mg/kg po each (25,26). Compound 9 had an MED value of 0.01 mg/kg po compared to 3 mg/kg po for 8.
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