Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists.
This study completes a series of papers devoted to the characterization of the non-competitive mGluR2/3 antagonist properties of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives with particular emphasis on derivatizations compatible with brain penetration and in vivo activity. Especially the compounds bearing a para-pyridine consistently showed in vivo activity in rat behavioral models after oral administration, for example, blockade of the mGluR2/3 agonist LY354740-induced hypoactivity and improvement of a working memory deficit induced either by LY354740 or scopolamine in the delayed match to position task (DMTP). Moreover, combination studies with a cholinesterase inhibitor show apparent synergistic effects on working memory impairment induced by scopolamine.
Woltering
Thomas J
TJ
Discovery Chemistry, F. Hoffmann-La Roche Ltd, Basel, Switzerland. thomas.woltering@roche.com
Wichmann
Jürgen
J
Goetschi
Erwin
E
Knoflach
Frédéric
F
Ballard
Theresa M
TM
Huwyler
Jörg
J
Gatti
Silvia
S
D000284:Administration, Oral; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal; D001570:Benzodiazepinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012601:Scopolamine / Q000494:pharmacology
C574444:4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo(b)(1,4)diazepin-2-one; D001381:Azepines; D001570:Benzodiazepinones; D001643:Bridged Bicyclo Compounds; D002800:Cholinesterase Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D012601:Scopolamine; C104753:eglumetad