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Titolo:
Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid
Autore:
Moller, EH; Egebjerg, J; Brehm, L; Stensbol, TB; Johansen, TN; Madsen, U; Krogsgaard-Larsen, P;
Indirizzi:
Royal Danish Sch Pharm, Dept Med Chem, PharmaBiotec Neurosci Res Ctr, DK-2100 Copenhagen, Denmark Royal Danish Sch Pharm Copenhagen Denmark DK-210000 Copenhagen, Denmark Univ Aarhus, Dept Biol Mol & Struct, DK-8000 Aarhus C, Denmark Univ Aarhus Aarhus Denmark C iol Mol & Struct, DK-8000 Aarhus C, Denmark
Titolo Testata:
CHIRALITY
fascicolo: 10, volume: 11, anno: 1999,
pagine: 752 - 759
SICI:
0899-0042(1999)11:10<752:RASAEO>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
EXCITATORY AMINO-ACIDS; METHYL-D-ASPARTATE; GLUTAMATE RECEPTORS; ALZHEIMERS-DISEASE; IBOTENIC ACID; PHARMACOLOGY; AMPA; AFFINITY; CHANNEL; KAINATE;
Keywords:
(S)- and (R)-ATPO; chiral HPLC; X-ray crystallography; cloned ionotropic glutamate receptors; GluR1-4; GluR5 antagonist;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Krogsgaard-Larsen, P Royal Danish Sch Pharm, Dept Med Chem, PharmaBiotec Neurosci Res Ctr, 2 Univ Pk, DK-2100 Copenhagen, Denmark Royal Danish Sch Pharm 2 Univ Pk Copenhagen Denmark DK-2100
Citazione:
E.H. Moller et al., "Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid", CHIRALITY, 11(10), 1999, pp. 752-759

Abstract

The phosphono amino acid, (RS)-2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl] propionic acid (ATPO), is a structural hybrid between the NMDA antagonist (RS)-2-amino-7-phosphonoheptanoic acid (AP7) and the AMPA and GluR5 agonist, (RS)-2-amino-3-(5-tert-butyl-3-hydroxy-4-isoxazolyl) propionic acid (ATPA). ATPO has been resolved into (S)-ATPO and (R)-ATPO using chiral HPLC, and the absolute stereochemistry of the two enantiomers was established by an X-ray crystallographic analysis of (R)-ATPO. (S)-ATPO and (R)-ATPO were characterized pharmacologically using rat brain membrane binding and electrophysiologically using the cortical wedge preparation as well as homo- or heteromeric GluR1-4, GluR5-6, and KA2 receptors expressed in Xenopus oocytes. (R)-ATPO was essentially inactive as an agonist or antagonistin all test systems. (S)-ATPO was an inhibitor of the binding of [H-3]AMPA(IC50 = 16 +/- 1 mu M) and of [H-3]-6-cyano-7-nitroquinoxaline-2,3-dione ([H-3]CNQX) (IC50 = 1.8 +/- 0.2 mu M), but was inactive in the [H-3]kainic acid and the [H-3]-(RS)-3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid([H-3]CPP) binding assays. (S)-ATPO did not show detectable agonist effects at any of the receptors under study, but antagonized AMPA-induced depolarization in the cortical wedge preparation (IC50 = 15 +/- 1 mu M). (S)-ATPO also blocked kainic acid agonist effects at GluR1 (K-i = 2.0 mu M), GluR1+2(K-i = 3.6 mu M), GluR3 (K-i = 3.6 mu M), GluR4 (K-i = 6.7 mu M), and GluR5 (K-i = 23 mu M), but was inactive at GluR6 and GluR6+KA2. Thus, although ATPO is a structural analog of AP7 neither (S)-ATPO nor (R)-ATPO are recognized by NMDA receptor sites. Chirality 11:752-759, 1999. (C) 1999 Wiley-Liss, Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 23:03:58