Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists |
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Authors: | Woltering Thomas J Wichmann Jürgen Goetschi Erwin Adam Geo Kew James N C Knoflach Frédéric Ballard Theresa M Huwyler Jörg Mutel Vincent Gatti Silvia |
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Affiliation: | F. Hoffmann-La Roche Ltd., Pharma Discovery Chemistry CNS, CH-4070 Basel, Switzerland. thomas.woltering@roche.com |
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Abstract: | A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of the (2-aryl)-ethynyl-moiety in 8-position with smaller less lipophilic substituents produced compounds inhibiting the binding of [3H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. These compounds were able to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus and in vivo activity could be demonstrated by reversal of the LY354740-induced hypoactivity in mice after oral administration. |
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