Studies on cerebral protective agents. IX. Synthesis of novel 1,2,3,4-tetrahydroisoquinolines as N-methyl-D-aspartate antagonists.
A series of 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for anticonvulsant activity against intracerebro-ventriculas (i.c.v.) N-methyl-D-aspartate (NMDA)-induced seizures in mice. Among these compounds, (+)-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride ((+)-1a, FR115427) was the most effective anticonvulsant, and also protected CA1 hippocampal neurons from ischemia-induced neuronal degeneration in rats at 32 mg/kg i.p. In addition, (+)-1a showed anti-hypoxic activity in mice at 3.2-32 mg/kg i.p. The absolute configuration at the C-1 position of the isoquinoline ring was determined to be S by a single-crystal X-ray analysis of (+)-1a (+)-di-p-toluoyl-D-tartrate. Structure-activity relationships with regard to the anticonvulsant activity of this series of compounds are discussed, and the three-dimensional structures of (S)-(+)-1a and MK801 are compared.
Ohkubo
M
M
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan.
Kuno
A
A
Katsuta
K
K
Ueda
Y
Y
Shirakawa
K
K
Nakanishi
H
H
Nakanishi
I
I
Kinoshita
T
T
Takasugi
H
H
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy; D018360:Crystallography, X-Ray; D016291:Dizocilpine Maleate / Q000737:chemistry / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D044005:Tetrahydroisoquinolines; C084456:1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline; D016291:Dizocilpine Maleate