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Titolo:
STRUCTURE-ACTIVITY STUDIES OF 6-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .2. EFFECTS OF DISTAL ACID BIOISOSTERIC SUBSTITUTION, ABSOLUTE STEREOCHEMICAL PREFERENCES, AND IN-VIVO ACTIVITY
Autore:
ORNSTEIN PL; ARNOLD MB; ALLEN NK; BLEISCH T; BORROMEO PS; LUGAR CW; LEANDER JD; LODGE D; SCHOEPP DD;
Indirizzi:
ELI LILLY & CO,LILLY CORP CTR,LILLY RES LABS,DC 0510 INDIANAPOLIS IN 46285 LILLY RES CTR LTD WINDLESHAM GU20 6PH SURREY ENGLAND
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 11, volume: 39, anno: 1996,
pagine: 2232 - 2244
SICI:
0022-2623(1996)39:11<2232:SSO6D>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHENCYCLIDINE-LIKE DRUGS; METHYL-D-ASPARTATE; BINDING; BRAIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
22
Recensione:
Indirizzi per estratti:
Citazione:
P.L. Ornstein et al., "STRUCTURE-ACTIVITY STUDIES OF 6-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .2. EFFECTS OF DISTAL ACID BIOISOSTERIC SUBSTITUTION, ABSOLUTE STEREOCHEMICAL PREFERENCES, AND IN-VIVO ACTIVITY", Journal of medicinal chemistry, 39(11), 1996, pp. 2232-2244

Abstract

We have explored the excitatory amino acid antagonist activity in a series of decahydroisoquinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist azol-5-yl)ethyl)decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds. We have already shown that 1had the optimal stereochemical array and that AMPA antagonist activity was maximized for a two-carbon spacer separating a tetrazole from the bicyclic nucleus. In this paper, we explored the effects of varying the distal acid and the absolute stereochemical preferences of many ofthese analogs. We looked at a variety of different acid bioisosteres,including 5-membered hetereocyclic acids such as tetrazole, 1,2,4-triazole, and 3-isoxazolone; carboxylic, phosphonic, and sulfonic acid; and acyl sulfonamides. Compounds were evaluated in rat cortical tissue for their ability to inhibit the binding of radioligands selective forAMPA ([H-3]AMPA), NMDA ([H-3]CGS 19755), and kainic acid ([H-3]kainicacid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 mu M), NMDA (40 mu M), and kainic acid (10 mu M). A number of compounds from this and the preceding paper were also evaluated in mice for their ability to block maximal electroshock-induced convulsions and ATPA-induced rigidity in mice.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 04:12:35