STUDIES ON CEREBRAL PROTECTIVE AGENTS .9. SYNTHESIS OF NOVEL 1,2,3,4-TETRAHYDROISOQUINOLINES AS N-METHYL-D-ASPARTATE ANTAGONISTS

A series of 1,2,3,4-tetrahydroisoquinoline derivatives were synthesize d and evaluated for anticonvulsant activity against intracerebro-ventr iculas (i.c.v.) N-methyl-D-aspartate (NMDA)-induced seizures in mice, Among these compounds, )-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinol ine hydrochloride ((+)-1a, FR115427) was the most effective anticonvul sant, and also protected CAI hippocampal neurons from ischemia-induced neuronal degeneration in rats at 32 mg/kg i.p. In addition, (+)-1a sh owed anti-hypoxic activity in mice at 3.2-32 mg/kg i.p. The absolute c onfiguration at the C-1 position of the isoquinoline ring was determin ed to be S by a single-crystal X-ray analysis of(+)-1a(+)-di-p-toluoyl -D-tartrate. Structure-activity relationships with regard to the antic onvulsant activity of this series of compounds are discussed, and the three-dimensional structures of (S)-(+)-1a and MK801 are compared.