Cerebroprotective and anticonvulsant action of competitive and non-competitive NMDA antagonists

Chapman, A. Chaston; Swan, Jeanette H.; Patel, Smita S.; Graham, Joanne L.; Meldrum, Brian S.

doi:10.1007/978-94-011-2262-7_25

Cited by 6 publications

(5 citation statements)

References 48 publications

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“…Since there is a wider range between anticataleptic effects and the unwanted stereotyped effects, predictive for psychotomimetic side effects in humans. A similar effect is shown for antiepileptic and antiischemic effects of NMDA antagonists (Chapman et al, 1990). On the other hand, the competitive NMDA antagonists do not have the locomotion (kinesia) inducing effects of non-competitive antagonists.…”

Section: Discussionmentioning

confidence: 58%

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior

Kretschmer

Zadow

Volz

et al. 1992

J. Neural Transmission

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The effects of competitive (CGP 37849 and CGP 39551) and non-competitive (dizocilpine) N-methyl-D-aspartate (NMDA) antagonists were tested in three animal models (catalepsy, sniffing, locomotion) and, in addition, the modulation of these effects by an agonist of the strychnine-insensitive glycine binding site was investigated. Both competitive and non-competitive NMDA antagonists reduced neuroleptic-induced catalepsy. Weak sniffing was induced by the competitive antagonist but strong sniffing by the non-competitive NMDA antagonist. Due to muscle relaxation the competitive antagonist reduced locomotion, in contrast to stimulation of locomotor activity induced by the non-competitive NMDA antagonist. The glycine agonist (D-cycloserine) potentiated the effects of the non-competitive but antagonized those of the competitive NMDA antagonist.

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Section: Discussionmentioning

confidence: 58%

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior

Kretschmer

Zadow

Volz

et al. 1992

J. Neural Transmission

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“…Accordingly, both types of glutamate antagonists differentially affect the cerebral glucose metabolism which is decreased and increased by, respectively, AMPA antagonists and non-competitive NMDA antagonists (Chapman et al, 1990;Browne and McCulloch, 1994). In contrast to NMDA antagonists (Bischoff and Tiedtke, 1992), AMPA antagonists do not produce any learning deficits in mice and rats (Hauber, 1994;Parada et al, 1994).…”

Section: Discussionmentioning

confidence: 95%

Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats

Bubser

Tzschentke

Hauber

1995

J. Neural Transmission

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The behavioural and neurochemical effects of the N-methyl-D-aspartate (NMDA) antagonist dizocilpine and the alpha-amino-3-hydroxy-5-methylisoxazole- 4-propionic acid (AMPA) antagonist GYKI 52466, given alone or in combination, were investigated in rats. Locomotor activity was increased by dizocilpine (0.2 mg/kg), but not by GYKI 52466 (2.4 mg/kg). Dizocilpine-induced hyperlocomotion was reduced by co-administration of GYKI 52466. In dizocilpine-treated rats dopamine (DA) metabolism (measured as DOPAC [dihydroxyphenylacetic acid] or DOPAC/DA in post mortem brain tissue) was increased in the prefrontal cortex and nucleus accumbens. In GYKI 52466-treated rats serotonin was reduced in the prefrontal cortex and nucleus accumbens while DA metabolism was not affected. In rats treated with dizocilpine plus GYKI 52466, DA metabolism was increased only in the prefrontal cortex, but not in the nucleus accumbens, when compared with vehicle-treated animals. These data confirm that AMPA and NMDA antagonists do not have synergistic effects on locomotor activity. A differential role of NMDA and AMPA antagonists in the control of mesolimbic DA neurons will be discussed here.

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“…The parent compound, AP5, is a relatively weak anticonvulsant both in DBA/2 mice (ED,, clonic = 320 pmol/kg) and in baboons (fully protective dose 3.3 pmol/kg i.v.) (Chapman et al, 19906). The more rigid molecule produced by the double bonds in CGP 37849 and CGP 39551 may, by analogy with the potent, rigid, piperazine (CPP, CPPene) and piperidine (CGS 19755) analogues of AP5 and AP7, contribute to their greater affinities at the NMDA receptor and hence their greater anticonvulsant potencies.…”

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Activity of Two Orally Active Competitive N‐Methyl‐D‐Aspartate Antagonists, CGP 37849 and CGP 39551, Against Sound‐Induced Seizures in DBA/2 Mice and Photically Induced Myoclonus in Papio papio

et al. 1991

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Two novel N-methyl-D-aspartate (NMDA) antagonists, DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid CPG 37849 and the corresponding 1-ethyl ester CGP 39551, were tested as anticonvulsants in DBA/2 mice and photosensitive Senegalese baboons, Papio papio. In DBA/2 mice, CGP 37849 is more potent than CGP 39551 when administered intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) (ED50 for suppression of clonic seizures at 60 min: i.c.v. 0.038 and 0.21 nmol; i.p. 3.40 and 19.1 mumol/kg, respectively). When administered orally in mice, the two compounds are approximately equipotent (ED50 CGP 37849, 35.2 mumol/kg; ED50 CGP 39551, 28.1 mumol/kg). The time course of action of CGP 39551 is exceptionally prolonged: 42 mumol/kg i.p. protects against clonic seizures for 48 h. Protection provided by other NMDA antagonists in mice is of much shorter duration: 2-amino-5-phosphono-pentanoic acid (AP5) 1 h, 2-amino-7-phosphono-heptanoic acid (AP7) 4 h, 2-amino-7-phosphono-heptanoic acid 1-ethyl ester 3 h, 4-(3-phosphonopropyl)-2-piperazine carboxylic acid (CPP) 2 h, cis-4-(phosphonomethyl)-2-piperidine-carboxylic acid (CGS 19755) 4 h, and CGP 37849 4 h. After oral administration of the drugs, the therapeutic index (TI = ratio of the ED50 values for rotorod performance and anticonvulsant protection) remains relatively constant at 5.9-7.2 for 3 h (CGP 37849) and 4.0-6.1 for 24 h (CGP 39551). After i.p. administration, the TI values are CGP 37849 at 1 h 2.4, and at 3 h 20.0, CGP 39551 at 1 h 2.3, at 3 h 7.1, and at 24 h 3.6. In baboons, acute administration of CGP 37849 at doses of 48-191 mumol/kg intravenously (i.v.) suppresses photically induced myoclonus for at least 285 min, with severe side effects at the highest dose tested. CGP 39551 at doses of 169-675 mumol/kg i.v. shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). CGP 37849 at 48-96 mumol/kg orally (p.o.) fails to protect against photically induced myoclonus up to 4 h after administration, but 191 mumol/kg (40 mg/kg) p.o. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 mumol/kg (40 mg/kg) p.o. produces total suppression of seizure activity at 4 h with a longer duration of anticonvulsant action (2-3 days).(ABSTRACT TRUNCATED AT 400 WORDS)

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Cerebroprotective and anticonvulsant action of competitive and non-competitive NMDA antagonists

Cited by 6 publications

References 48 publications

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior

The contribution of the different binding sites of the N-methyl-D-aspartate (NMDA) receptor to the expression of behavior

Behavioural and neurochemical interactions of the AMPA antagonist GYKI 52466 and the non-competitive NMDA antagonist dizocilpine in rats

Anticonvulsant Activity of Two Orally Active Competitive N‐Methyl‐D‐Aspartate Antagonists, CGP 37849 and CGP 39551, Against Sound‐Induced Seizures in DBA/2 Mice and Photically Induced Myoclonus in Papio papio

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