CGP 37849 / CGP 39551: The First Competitive NMDA Receptor Antagonists Suitable for Oral Antiepileptic Therapy

Schmutz, M.; Portet, C.; Olpe, Hans‐Rudolf; Klebs, K.; Jeker, A.; Heckendorn, Roland; Fagg, Graham E.; Allgeier, Hans

doi:10.1007/978-3-642-46732-5_46

Physiology, Pharmacology and Development of Epileptogenic Phenomena 1991

DOI: 10.1007/978-3-642-46732-5_46

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CGP 37849 / CGP 39551: The First Competitive NMDA Receptor Antagonists Suitable for Oral Antiepileptic Therapy

M. Schmutz¹,

C. Portet²,

Hans‐Rudolf Olpe³

et al.

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“…shows weak anticonvulsant activity only at the highest dose tested (accompanied by severe side effects). The possible clinical use of this group of com-pounds was recently enhanced by the description of a pair of orally active, long-acting, competitive NMDA antagonists, ~~-(E)-2-amino-4-methyl-5phosphono-3-pentenoic acid (CGP 37849) and the corresponding 1-ethyl ester (CGP 39551) (Fagg et at., 1988;Schmutz et al, 1988Schmutz et al, , 1990Fagg et al, 1990b). fails to protect against photically induced myoclonus up to 4 h after administration, but 191 p,mol/kg (40 mg/kg) p.0.…”

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confidence: 99%

“…CGP 37849 at 48-96 pmol/kg orally (p.0.) T h e s e c o m p o u n d s a r e unsaturated branched analogues of 2-amino-5-phosphonopentanoic acid (AP5) and protect against electroshock-induced seizures when administered to mice and rats (Schmutz et al, 1988(Schmutz et al, , 1989(Schmutz et al, , 1990. produces complete suppression of seizures after 24 h. On the other hand, CGP 39551 at 169 pmol/kg (40 mg/kg) p.0.…”

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confidence: 99%

“…fails to protect against photically induced myoclonus up to 4 h after administration, but 191 p,mol/kg (40 mg/kg) p.0. CGP 3955 1 also delays development of rat amygdaloid kindling (Schmutz et al, 1988(Schmutz et al, , 1989(Schmutz et al, , 1990. produces total suppression of seizure activity at 4 h with a longer duration of anticonvuhant action (2-3 days).…”

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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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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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CGP 37849 / CGP 39551: The First Competitive NMDA Receptor Antagonists Suitable for Oral Antiepileptic Therapy

Cited by 1 publication

References 12 publications

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

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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