POTENT, ORALLY-ACTIVE, COMPETITIVE N-METHYL-D-ASPARTATE (NMDA) RECEPTOR ANTAGONISTS ARE SUBSTRATES FOR A NEUTRAL AMINO-ACID-UPTAKE SYSTEM IN CHINESE-HAMSTER OVARY CELLS

A series of enantiomerically pure (phosphonomethyl)-substituted phenyl alanine derivatives related to SDZ EAB 515 (1) were prepared as compet itive N-methyl-D-aspartate (NMDA) receptor antagonists. Unlike most kn own competitive NMDA antagonists, analogs in this series with the S-co nfiguration are potent NMDA antagonists whereas analogs with the unnat ural R-configuration are weak NMDA antagonists, as determined by recep tor binding experiments and their anticonvulsant action in mice. Exami nation in a previously reported competitive NMDA pharmacophore model r evealed that receptor affinity can be explained partially by a cavity that accommodates the biphenyl ring of 1, while the biphenyl ring of t he R-enantiomer 2 extends into a disallowed steric region. We proposed that analogs with the natural S-configuration and a large hydrophobic moiety would have an advantage in vivo over analogs with an R-configu ration by being able to use a neutral amino acid uptake system to enha nce both peripheral adsorption and transport into the brain. Examinati on in a system L neutral amino acid transport carrier assay shows that 1 competes with L-Phe for transport in an apparent competitive and st ereospecific manner (estimated K-i = 50 mu M). The 1- and 2-naphthyl d erivatives 3a,3b were found to be among the most potent, competitive N MDA antagonists yet discovered, being ca. 15-fold more potent than 1 i n. vitro and in vivo, with a long duration of action. The title compou nd 3a had potent oral activity in MES (ED(50) = 5.0 mg/kg). 3a also re tains its ability to compete, albeit more weakly than 1 (estimated K-i = 200 mu M), for L-Phe uptake to CHO cells. In this series, analogs w ith the R-configuration are not substrates for the system L neutral am ino acid transport carrier. These results provide evidence that centra l nervous system active agents can be designed as substrates of a neut ral amino acid transporter as a means to enhance penetration of the bl ood-brain barrier.