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 phenylalanine derivatives related to SDZ EAB 515 (1) were prepared as competitive N-methyl-D-aspartate (NMDA) receptor antagonists. Unlike most known competitive NMDA antagonists, analogs in this series with the S-configuration are potent NMDA antagonists whereas analogs with the unnatural R-configuration are weak NMDA antagonists, as determined by receptor binding experiments and their anticonvulsant action in mice. Examination in a previously reported competitive NMDA pharmacophore model revealed that receptor affinity can be explained partially by a cavity that accommodates the biphenyl ring of 1, while the biphenyl ring of the 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-configuration by being able to use a neutral amino acid uptake system to enhance both peripheral adsorption and transport into the brain. Examination in a system L neutral amino acid transport carrier assay shows that 1 competes with L-Phe for transport in an apparent competitive and stereospecific manner (estimated Ki = 50 microM). The 1- and 2-naphthyl derivatives 3a,3b were found to be among the most potent, competitive NMDA antagonists yet discovered, being ca. 15-fold more potent than 1 in vitro and in vivo, with a long duration of action. The title compound 3a had potent oral activity in MES (ED50 = 5.0 mg/kg). 3a also retains its ability to compete, albeit more weakly than 1 (estimated Ki = 200 microM), for L-Phe uptake to CHO cells. In this series, analogs with the R-configuration are not substrates for the system L neutral amino acid transport carrier. These results provide evidence that central nervous system active agents can be designed as substrates of a neutral amino acid transporter as a means to enhance penetration of the blood-brain barrier.
Li
J H
JH
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Bigge
C F
CF
Williamson
R M
RM
Borosky
S A
SA
Vartanian
M G
MG
Ortwine
D F
DF
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D026905:Amino Acid Transport Systems; D000596:Amino Acids / Q000493:pharmacokinetics*; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism; D006224:Cricetinae; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011422:Propionates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014316:Tritium
D026905:Amino Acid Transport Systems; D000596:Amino Acids; D001713:Biphenyl Compounds; D002352:Carrier Proteins; D011422:Propionates; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; C077642:2-amino-5-phosphonomethyl(1,1'-biphenyl)-3-propanoic acid; C069052:CGP 39653; D018698:Glutamic Acid; D010649:Phenylalanine; D015763:2-Amino-5-phosphonovalerate; D005998:Glycine