Allosteric Potentiators of the Metabotropic Glutamate Receptor 2 (mGlu2). Part 1. Identification and Synthesis of Phenyl-tetrazolyl Acetophenones.

Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA.
Bioorganic & Medicinal Chemistry Letters (Impact Factor: 2.33). 12/2004; 14(21):5329-32. DOI: 10.1016/j.bmcl.2004.08.020
Source: PubMed

ABSTRACT We have identified and synthesized a series of aryl-tetrazoyl acetophenones as positive allosteric potentiators of the metabotropic glutamate receptor 2. Structure activity relationship studies directed toward improving the potency and level of potentiation led to the discovery of 22 (EC(50)=93nM, 128% potentiation).

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    • "These compounds show selectivity for mGluR2 compared with other mGluR subtypes (Johnson et al, 2003, 2005; Schaffhauser et al, 2003; Galici et al, 2006) and bind at an allosteric site on the receptor to potentiate glutamateinduced activation of the receptor (Schaffhauser et al, 2003). mGluR2 PAMs have some of the same behavioral effects as mGlu2/3 agonists in animal tests used to assess anxiolytic and antipsychotic activity (Johnson et al, 2003, 2005; Schaffhauser et al, 2003; Pinkerton et al, 2004; Bonnefous et al, 2005; Galici et al, 2005, 2006; Govek et al, 2005; Benneyworth et al, 2007). These findings are consistent with recent reports showing that mGluR2, but not mGluR3, mediates the actions of the mGluR2/3 agonist LY379268 in mouse tests predictive of antipsychotic activity (Woolley et al, 2008). "
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