New beta-hydroxyaspartate derivatives are competitive blockers for the bovine glutamate/aspartate transporter.
J Biol Chem
; 272(33): 20336-9, 1997 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-9252337
ABSTRACT
Four subtypes of excitatory amino acid transporters (EAAT1-4) have been identified in the mammalian brain. A number of pharmacological agents have been developed to study their intrinsic properties and function. Up to now, blockers were available only for EAAT2, whereas all the inhibitors of glutamate uptake active on the other subtypes were proved to be substrates of the transporters. We synthesized five new derivatives of DL-threo-beta-hydroxyaspartic acid, a well known general substrate of EAATs, and investigated their potential blocking activity on the cloned bovine EAAT1 expressed in the Xenopus oocyte system, by using radiotracer and voltage-clamp techniques. Two of our derivatives proved to be substrates for bovine EAAT1, with reduced electrogenicity compared with their parent compound, and an affinity of 40 and 64 microM. The last three derivatives displayed a blocking activity on bovine EAAT1. The affinity of DL-threo-beta-benzoyloxyaspartate and DL-threo-beta-(1-naphthoyl)oxyaspartate was determined by Schild analysis as 17.2 and 52.1 microM, respectively. These blockers should help in the better understanding of the key intrinsic properties of EAAT1. Moreover, they appear as good candidates for a general blocking activity on EAATs.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Aspartic Acid
/
ATP-Binding Cassette Transporters
Limits:
Animals
Language:
En
Journal:
J Biol Chem
Year:
1997
Document type:
Article
Affiliation country:
Japan