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Titolo:
BIPHENYL-DERIVATIVES OF 2-AMINO-7-PHOSPHONOHEPTANOIC ACID, A NOVEL CLASS OF POTENT COMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS .2. PHARMACOLOGICAL CHARACTERIZATION IN-VIVO
Autore:
URWYLER S; CAMPBELL E; FRICKER G; JENNER P; LEMAIRE M; MCALLISTER KH; NEIJT HC; PARK CK; PERKINS M; RUDIN M; SAUTER A; SMITH L; WIEDERHOLD KH; MULLER W;
Indirizzi:
SANDOZ RES INST BERNE LTD CH-3001 BERN SWITZERLAND SANDOZ INST MED RES LONDON WC1E 6BN ENGLAND SANDOZ PHARMA LTD,DRUG SAFETY & PRECLIN RES CH-4002 BASEL SWITZERLAND UNIV LONDON KINGS COLL,DEPT PHARMACOL LONDON WC2R 2LS ENGLAND CATHOLIC UNIV,DEPT NEUROSURG,COLL MED SEOUL SOUTH KOREA
Titolo Testata:
Neuropharmacology
fascicolo: 6, volume: 35, anno: 1996,
pagine: 655 - 669
SICI:
0028-3908(1996)35:6<655:BO2AAN>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
ETHANOL WITHDRAWAL SEIZURES; CEREBRAL-ARTERY OCCLUSION; PARKINSONS-DISEASE; NMDA-ANTAGONIST; BASAL GANGLIA; NEURODEGENERATIVE DISEASE; THERMAL HYPERALGESIA; QUINOLINIC ACID; ANIMAL-MODELS; SCIATIC-NERVE;
Keywords:
BIPHENYL-AP7-DERIVATIVES; ANTICONVULSANTS; NEUROPROTECTION; ISCHEMIA; EXCITOTOXICITY; ANALGESIA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
S. Urwyler et al., "BIPHENYL-DERIVATIVES OF 2-AMINO-7-PHOSPHONOHEPTANOIC ACID, A NOVEL CLASS OF POTENT COMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS .2. PHARMACOLOGICAL CHARACTERIZATION IN-VIVO", Neuropharmacology, 35(6), 1996, pp. 655-669

Abstract

A selection of biphenyl-analogues of 2-amino-7-phosphonoheptanoic acid (AP7), N-methyl-D-aspartate (NMDA) receptor antagonists with high affinity in vitro, were evaluated to assess their in vivo efficacy. The lead compound SDZ EAB 515 was found to inhibit L-phenylalanine uptake by the large neutral amino acid carrier in vitro and in vivo; active transport may thus confer a good bioavailability to this class of compounds. CNS effects were demonstrated by significant changes in 2-deoxyglucose-uptake in various brain regions at doses from 1 to 10 mg/kg i.p. With the most active agent, SDZ 220-581, full protection against maximal electroshock seizures (MES) was obtained at oral doses of 10 mg/kg in rats and in mice. The compound had a fast onset (less than or equal to 1 hr) and a long duration (greater than or equal to 24 hr) of action. Motor-debilitating effects (impairment of rotarod performance) occurred at doses about 10 times higher than those required for protection against MES. Neuroprotective activity was demonstrated by the ability of the compounds to reduce the extent of quinolinic acid-induced striatal lesions in rats, in the dose range of 3-15 mg/kg (i.p.) or 10-50 mg/kg (p.o.). In the middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia in rats, the test compounds reduced the infarct size by 40-50% when given i.v. before or by 20-30% when given i.v. 1 hr after MCAO. SDZ 220-581 provided 20-30% protection at greater than or equal to 2 x 10 mg/kg p.o. This compound also showed analgesic activity at low oral doses in a model of neuropathic pain, although higher doses were required in a model of mechanical inflammatory hyperalgesia. Unexpectedly, SDZ 220-581 at low s.c. doses counteracted the antiparkinsonian effects of L-DOPA in MPTP-treated marmosets. (Sub)chronic administration of SDZ 220-581 did not reduce its ability to protectagainst quinolinic acid neurotoxicity, and no upregulation of NMDA receptors was detected using a [H-3] CGP-39653 binding assay. In conclusion, from a series of biphenyl-AP7-derivatives, SDZ 220-581 is clearlythe most active compound in vivo. Its pharmacological profile with a good, long-lasting oral activity might open up novel therapeutic applications for competitive NMDA receptor antagonists. Copyright (C) 1996 Published by Elsevier Science Ltd

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Documento generato il 04/04/20 alle ore 02:37:52