dizocilpine-maleate and 1-methyl-1-phenyl-1-2-3-4-tetrahydroisoquinoline

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.

Topics: Animals; Anticonvulsants; Brain Ischemia; Crystallography, X-Ray; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hippocampus; Hypoxia; Isoquinolines; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Molecular Structure; Neuroprotective Agents; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Structure-Activity Relationship; Tetrahydroisoquinolines

Recent studies indicate that competitive and non-competitive NMDA receptor antagonists can be readily distinguished by their effects on local cerebral glucose utilisation (1CGU). In the present study we compare the effects of the novel NMDA antagonist, (+)-1-methyl-1phenyl-1,2,3,4-tetrahydroisoquinoline (FR115427) on 1CGU, comparing its metabolic profile with that of the non-competitive NMDA receptor antagonist, dizocilpine (MK801) and of the competitive NMDA receptor antagonist CGS19755, using the 2-deoxyglucose metabolic mapping approach. Local cerebral glucose utilisation was measured in 80 anatomically discrete regions of the conscious rat brain using [14C]2-deoxyglucose quantitative autoradiography. Studies were initiated 10 min after the administration of FR115427 (0.1-3 mg/kg i.v.; n = 20), dizocilpine (0.03-0.3 mg/kg; n = 15), CGS19755 (1-30 mg/kg; n = 15) or saline (2 ml/kg; n = 5). Dizocilpine produced characteristic alterations in 1CGU with widespread increases in 1CGU in primary olfactory and limbic areas while reducing 1CGU in somatosensory and motor cortex. FR115427 produced a pattern of altered 1CGU which was broadly similar to that elicited by dizocilpine with increases in 1CGU in the pontine nuclei, presubiculum and hippocampus and reductions in somatosensory and motor cortex and within components of the auditory system. However, FR115427 was approximately 30-fold less potent than dizocilpine in this regard. In limbic structures, the effects of FR115427 were less pronounced than those produced by dizocilpine. Increases in 1CGU of 62-98% were found in retrosplenial, piriform and entorhinal cortex of dizocilpine-treated rats whereas these areas appeared relatively unaffected following FR115427 administration. A comparison of the pattern of metabolic response produced by each of these agents was performed by constructing a hierarchy of regional responsiveness using the f statistic: while focal differences in the metabolic profiles of dizocilpine and FR115427 were evident, a plot of the regional f values for dizocilpine and FR115427 revealed a strong overall relationship between the metabolic responses with a Pearson's product moment correlation of 0.78. In contrast, the correlation between the patterns produced by CGS19755 and that for dizocilpine or FR115427 was poor (r = 0.28 and 0.5 respectively).

Topics: Animals; Autoradiography; Behavior, Animal; Binding, Competitive; Brain; Brain Chemistry; Cerebral Cortex; Deoxyglucose; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extrapyramidal Tracts; Glucose; Hippocampus; Isoquinolines; Limbic System; Pipecolic Acids; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

Primary culture of cerebral cortical neurons from mouse embryo was treated with non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, FR115427 and MK801. Both FR115427 and MK801 at 1-10 microM promoted neuronal survival after 7 days cultivation, determined by calorimetric assay for acid phosphatase (AP) activity. FR115426, the (-) isomer of FR115427 also promoted neuronal survival. However, competitive NMDA antagonists, APH and CGS19755 did not show promotive effect on neuronal survival at up to 100 microM. Anti-NMDA activity of these compounds was evaluated using an NMDA-induced convulsion assay. The relative potency of anti-NMDA activity was CGS19755 > MK801 > APH > FR115427 > FR115426. These data suggest that the effects on neuronal survival by FR115427 and MK801 are independent of anti-NMDA activity.

Topics: Animals; Cell Survival; Cells, Cultured; Dizocilpine Maleate; Fibroblast Growth Factor 2; Isoquinolines; Mice; Neurons; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

Behavioral and in vitro receptor binding methods were used to evaluate and compare the effects of FR115427 ((+)-l-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline hydrochloride) with those of MK801, a non-competitive NMDA antagonist. FR115427 inhibited NMDA-induced convulsions in mice by intracerebroventrical(ICV) and systematic injection. FR115427 was found to be about ten times less potent than MK801. Furthermore, the inhibitory effect of FR115427 and MK801 on NMDA-induced convulsions was evaluated in time course studies in mice. MK801 exhibited a more sustained anticonvulsive activity than FR115427. In addition, PCP-like behaviors were examined in mice after ICV injection of these compounds. At the lowest dose FR115427 significantly increased locomotor activity, although the effect of this compound was about hundred times less potent than that of MK801. At higher dose a more complex pattern of behavior, e.g. head-movement and eventually ataxia was observed. In binding assays with rat brain membranes, FR115427 inhibited the binding of (3H)TCP (IC50 = 0.249 microM) and (3H)MK801 (IC50 = 0.312 microM) but did not inhibit the binding of (3H)CPP or (3H)glycine. These results suggest that FR115427 is a novel non-competitive NMDA antagonist that acts on a binding site located within the NMDA receptor associated ion channel.

Topics: Animals; Anticonvulsants; Behavior, Animal; Brain; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; In Vitro Techniques; Isoquinolines; Male; Membranes; Mice; Mice, Inbred ICR; Mice, Inbred Strains; Motor Activity; Phencyclidine; Piperazines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

The present study was carried out to compare the neuroprotective effect of the novel noncompetitive NMDA antagonist, FR115427, with that of(+)MK-801 in rat focal cerebral ischemia. Focal cerebral ischemia was produced by permanent occlusion of the left middle cerebral artery (MCA). Drugs were administered intraperitoneally immediately after ischemia and once a day for 6 successive days. FR115427 (10 mg/kg, i.p.) significantly improved neurologic deficit at 1 day after ischemia and reduced total infarct volume (54%) at 7 days after ischemia. Although FR115427 (10 mg/kg, s.c.) produced neuronal vacuolization similar to (+)MK-801, FR115427 did not produce adverse effects such as a loss of body weight, mortality, and hypothermia, in contrast to (+)MK-801. These results suggest that FR115427 may be useful in the treatment of stroke.

Topics: Animals; Brain Diseases; Brain Ischemia; Dizocilpine Maleate; Isoquinolines; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

Excitatory amino acids and their receptors have been postulated to be involved in mediating ischemic neuronal damage. We occluded the bilateral carotid arteries for 5 min in gerbils to examine the effect of FR115427, a novel N-methyl-D-aspartate (NMDA) antagonist, on ischemic neuronal damage. FR115427 prevented hippocampal CA1 cell damage at a dose of 10 mg/kg and reduced spontaneous locomotor hyperactivity in gerbils after the development of ischemia at a dose of 32 mg/kg. The effective doses of MK801 were 3.2 mg/kg for preventing hippocampal CA1 cell damage and 1 mg/kg for reducing spontaneous locomotor hyperactivity. Moreover, we monitored the changes in body temperature of ischemic gerbils for 24 hr. The body temperature of ischemic gerbils significantly increased 1 hr after reperfusion. The pretreatment with FR115427 or MK801 prevented the hyperthermia provoked 1 hr after reperfusion in ischemic gerbils. In addition, the hypothermia was developed in gerbils treated with MK801 24 hr after reperfusion. However, FR115427 did not show hypothermia at any time. These results indicate that FR115427 has a protective effect against ischemic hippocampal CA1 cell damage after systemic administration, and this protective effect appears to be due to anti-NMDA activity.

Topics: Animals; Body Temperature; Brain Ischemia; Dizocilpine Maleate; Gerbillinae; Hippocampus; Isoquinolines; Male; Motor Activity; N-Methylaspartate; Pyramidal Cells; Receptors, N-Methyl-D-Aspartate; Tetrahydroisoquinolines

The pharmacological profile of FR115427 has been examined using ligand binding and electrophysiological techniques. Binding of [3H]dizocilpine in the presence of L-glutamate was inhibited by the (+) isomers of dizocilpine and FR115427. The corresponding (-) isomers were less active, and stereoselectivity was particularly marked in the case of FR115427. In contrast to dizocilpine, the affinity of FR115427 for [3H]dizocilpine binding sites was little affected by addition of either L-glutamate and/or glycine. In a cortical wedge preparation, FR115427 inhibited N-methyl-D-aspartate (NMDA)-induced responses in a non-competitive, use-dependent manner. Intracellularly recorded excitatory synaptic responses in hippocampal neurones were only partially inhibited by FR115427 thereby confirming a selective effect on the NMDA-mediated component of neuronal excitation induced by the endogenous neurotransmitter. The data suggest that FR115427 is a non-competitive, use-dependent NMDA receptor antagonist with more pronounced stereoselectivity and less marked use dependence than dizocilpine.

Topics: Action Potentials; Animals; Binding, Competitive; Cerebral Cortex; Dizocilpine Maleate; Electrophysiology; Glutamates; Glutamic Acid; Glycine; In Vitro Techniques; Isoquinolines; Male; N-Methylaspartate; Neurons; Pyramidal Cells; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Stereoisomerism; Synaptic Transmission; Tetrahydroisoquinolines

The binding of [3H]FR115427 ([3H](+)-1-methyl-1-phenyl-1,2,3,4- tetrahydroisoquinoline) to rat cortical synaptosomal membranes was investigated. Binding was optimal at pH 7.4-8.0, and temperature had little effect on specific binding. Binding reached equilibrium within 30 min at 25 degrees C, and was reversible in the presence of excess unlabelled FR115427. [3H]FR115427 bound to a single population of non-interacting sites with an affinity of 45.4 +/- 3.9 nM, and a binding site density of 9.12 +/- 0.52 pmol/mg protein. The affinities of other N-methyl-D-aspartate (NMDA) receptor channel blockers for [3H]FR115427 binding sites were consistent with binding to a similar site to that occupied by dizocilpine. Binding was potentiated by L-glutamate and glycine with EC50 values of around 80 nM. In the presence of L-glutamate (10 microM), specific binding was increased 4-fold, whilst addition of glycine (10 microM) increased specific binding 2-fold. FR115427 exhibited marked stereoselectivity; (+)-FR115427 has 100-fold higher affinity than (-)-FR115427. This ligand may therefore be useful for the pharmacological investigation of the NMDA receptor ion channel.

Topics: Animals; Brain; Dizocilpine Maleate; Glutamates; Glycine; Hydrogen-Ion Concentration; In Vitro Techniques; Isoquinolines; Male; Membranes; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Synaptosomes; Tetrahydroisoquinolines