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Titolo:
NOVEL ANTICONVULSANT ANALOGS OF DEXTROMETHORPHAN - IMPROVED EFFICACY,POTENCY, DURATION AND SIDE-EFFECT PROFILE
Autore:
TORTELLA FC; ROBLES L; WITKIN JM; NEWMAN AH;
Indirizzi:
WALTER REED ARMY INST RES,DEPT MED NEUROSCI,NEUROPHARMACOL BRANCH WASHINGTON DC 20307 NIDA,ADDICT RES CTR,PSYCHOBIOL SECT,DRUG DEV GRP BALTIMORE MD 21224
Titolo Testata:
The Journal of pharmacology and experimental therapeutics
fascicolo: 2, volume: 268, anno: 1994,
pagine: 727 - 733
SICI:
0022-3565(1994)268:2<727:NAAOD->2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; GUINEA-PIG BRAIN; PHENCYCLIDINE-LIKE DRUGS; BINDING-SITES; PHARMACOLOGICAL FACTORS; LABORATORY EVALUATION; INDUCED CONVULSIONS; RECEPTOR LIGANDS; RAT-BRAIN; DEXTRORPHAN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
53
Recensione:
Indirizzi per estratti:
Citazione:
F.C. Tortella et al., "NOVEL ANTICONVULSANT ANALOGS OF DEXTROMETHORPHAN - IMPROVED EFFICACY,POTENCY, DURATION AND SIDE-EFFECT PROFILE", The Journal of pharmacology and experimental therapeutics, 268(2), 1994, pp. 727-733

Abstract

The anticonvulsant and neuroprotective activity of dextromethorphan (DM, [+]-3-methyl-17-methylmorphinan) may be, in part, due to its metabolism to the phencyclidine hydrochloride-like compound dextrorphan (DX). We evaluated the anticonvulsant activity and neurological impairingeffects in rats of three novel analogs of DM which, based upon their position-3 substituents, would either not be expected to be metabolized to DX or might do so at a reduced rate. The DM analogs were determined to be more potent and more efficacious than DM against maximal electroshock convulsions; two of the analogs, namely [(+)-3-ethoxy-17- methylmorphinan] and [(+)-3-(2-propoxy)-17-methylmorphinan], were equipotent to DX. [(+)3-Ethoxy-17-methylmorphinan] and L[(+)-3-(2-propoxy)-17-methylmorphinan) exhibited a duration of action (1-2 hr) slightly longer than DX (0.5-1 hr) and similar to DM (2-4 hr). The anticonvulsant effect of [(+)3-amino-17- methylmorphinan] persisted 4-6 hr. Against flurothyl convulsions DM was proconvulsant, DX was anticonvulsant and the DM analogs were inactive. In contrast, N-methyl-D-aspartate convulsions were antagonized by i.c.v. pretreatment with DM and the DM analogs, albeit with a potency approximately 10 times less than that of DX. Results of rotarod performance testing further distinguished the analogs from DM, DX or the anticonvulsant drug diazepam. No behavioral impairment was observed at the highest doses tested of each of the DM analogs, resulting in protective indices (i.e., rotarod TD50/maximal electroshock anticonvulsant ED(50)) greatly exceeding DM, DX or clinical anticonvulsant drugs. The results of this study establish these 3-substituted DM analogs as novel anticonvulsants exhibiting improved potency,efficacy, duration and side-effect profiles.

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Documento generato il 28/11/20 alle ore 04:41:28