Synthesis and characterization of 8-ethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: part 2. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists.
A series of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives was evaluated as non-competitive mGluR2/3 antagonists. Replacement of a cyano group by a five-membered heterocycle produced compounds inhibiting the binding of [(3)H]-LY354740 to rat mGluR2 with low nanomolar affinity and consistent functional effect at both mGluR2 and mGluR3. Further modification to improve the physicochemical properties led eventually to compounds with the ability to reverse LY354740-mediated inhibition of field excitatory postsynaptic potentials in the rat dentate gyrus.
Woltering
Thomas J
TJ
F. Hoffmann-La Roche Ltd, Pharma Discovery Chemistry, CH-4070 Basel, Switzerland. thomas.woltering@roche.com
Adam
Geo
G
Wichmann
Jürgen
J
Goetschi
Erwin
E
Kew
James N C
JN
Knoflach
Frédéric
F
Mutel
Vincent
V
Gatti
Silvia
S
D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015394:Molecular Structure; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
C525800:8-ethynyl-1,3-dihydro-benzo(b)(1,4)diazepin-2-one; D001381:Azepines; D001643:Bridged Bicyclo Compounds; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104753:eglumetad