SYNTHESIS OF RACEMIC 9-TETRAHYDRO-3-HYDROXY-1H-1-BENZAZEPINE-2,5-DIONES AS ANTAGONISTS OF N-METHYL-D-ASPARTATE (NMDA) AND LPHA-AMINO-3-HYDROXY-5-METHYLISOXAZOLE-4-PROPIONIC ACID (AMPA) RECEPTORS

The synthesis and pharmacological properties of several racemic 9-tetr ahydro-3-hydroxy-1H-1-benzazepine-2,5-diones (THHBADs) are described. Synthesis was accomplished via a Schmidt reaction with 5,6,7,8-tetrahy dro-2-methoxynaphthalene-1,4-diones (THMNDs) followed by demethylation . THMNDs were prepared via a Diels-Alder reaction with 2-methoxybenzoq uinone (5) or 2-bromo-5-methoxybenzoquinone (14) and substituted 1,3-b utadienes. The pharmacology of THHBADs was characterized by electrical recordings in Xenopus oocytes expressing rat brain NMDA and AMPA rece ptors. THHBADs are antagonists of NMDA and AMPA receptors with functio nal potency being dependent upon the substitution pattern on the tetra hydrobenzene moiety. The 7,8-dichloro-6-methyl (18a) and 7,8-dichloro- 6-ethyl (18b) analogs are the most potent THHBADs prepared and have ap parent antagonist dissociation constants (K-b values) of 0.0041 and 0. 0028 mu M, respectively, for NMDA receptors and 0.51 and 0.72 mu M, re spectively, for AMPA receptors.