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Titolo:
STRUCTURE-ACTIVITY STUDIES OF 6-(TETRAZOLYLALKYL)-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .1. EFFECTSOF STEREOCHEMISTRY, CHAIN-LENGTH, AND CHAIN SUBSTITUTION
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: 2219 - 2231
SICI:
0022-2623(1996)39:11<2219:SSO6D>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
COMPETITIVE NMDA ANTAGONISTS; METHYL-D-ASPARTATE; AMINO-ACIDS; MAXIMAL ELECTROSHOCK; GLUTAMATE ANTAGONIST; GLOBAL-ISCHEMIA; FOCAL ISCHEMIA; GYKI 52466; NBQX; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
51
Recensione:
Indirizzi per estratti:
Citazione:
P.L. Ornstein et al., "STRUCTURE-ACTIVITY STUDIES OF 6-(TETRAZOLYLALKYL)-SUBSTITUTED DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AMPA RECEPTOR ANTAGONISTS .1. EFFECTSOF STEREOCHEMISTRY, CHAIN-LENGTH, AND CHAIN SUBSTITUTION", Journal of medicinal chemistry, 39(11), 1996, pp. 2219-2231

Abstract

A series of 6-substituted decahydroisoquinoline-3-carboxylic acids were prepared as excitatory amino acid (EAA) receptor antagonists. Thesecompounds are antagonists at the N-methyl-D-aspartate (NMDA) and amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) subclasses of ligand gated ion channel (ionotropic) EAA receptors. ,4a,5,6,7,8,8a-decahydroisoquiinoline-3-carboxylic acid (9) is a potent, selective and systemically active AMPA antagonist. Other analogs from this series, including 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (32) and 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (61) are potent, selective, and systemically active NMDA antagonists. This and the subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry aroundthe hydroisoquinoline ring; of tetrahydro- versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms, the effect of heteroatom substitution in the position adjacent to the bicyclicnucleus and substitution with methyl or phenyl on the chain. Compounds were evaluated on rat cortical tissue for their ability to inhibit the binding of radioligands selective for AMPA ([H-3]AMPA), NMDA ([H-3]CGS 19755), and kainic acid ([H-3]- kainic acid) receptors and for their ability to inhibit depolarizations induced by AMPA (40 mu M), NMDA (40 mu M), and kainic acid (10 mu M). Our findings revealed that the optimal stereochemical array was the same for both NMDA (32 and 61) andAMPA (9) antagonists identified in this series and that the tetrahydroisoquinoline (25) and the C-1 carboxy (30) analogs of 9 are inactive. With a tetrazole in the distal acid position, an ethylene spacer (9) is optimal; substitution with oxygen or nitrogen on the chain in the position adjacent to the bicyclic nucleus significantly reduced activity, while substitution with a methyl or phenyl group on the chain was well tolerated.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/03/20 alle ore 13:31:11