Switch to
| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
11
|
| pubmed:dateCreated |
1995-7-18
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2-Amino-5-phosphonovalerate,
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acid Transport Systems,
http://linkedlifedata.com/resource/pubmed/chemical/Amino Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Biphenyl Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/CGP 39653,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Glutamic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/Glycine,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylalanine,
http://linkedlifedata.com/resource/pubmed/chemical/Propionic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, N-Methyl-D-Aspartate,
http://linkedlifedata.com/resource/pubmed/chemical/SDZ EAB 515,
http://linkedlifedata.com/resource/pubmed/chemical/Tritium
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-2623
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
26
|
| pubmed:volume |
38
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1955-65
|
| pubmed:dateRevised |
2005-11-17
|
| pubmed:meshHeading |
pubmed-meshheading:7783127-2-Amino-5-phosphonovalerate,
pubmed-meshheading:7783127-Amino Acid Transport Systems,
pubmed-meshheading:7783127-Amino Acids,
pubmed-meshheading:7783127-Animals,
pubmed-meshheading:7783127-Binding, Competitive,
pubmed-meshheading:7783127-Biphenyl Compounds,
pubmed-meshheading:7783127-CHO Cells,
pubmed-meshheading:7783127-Carrier Proteins,
pubmed-meshheading:7783127-Cricetinae,
pubmed-meshheading:7783127-Glutamic Acid,
pubmed-meshheading:7783127-Glycine,
pubmed-meshheading:7783127-Kinetics,
pubmed-meshheading:7783127-Magnetic Resonance Spectroscopy,
pubmed-meshheading:7783127-Membranes,
pubmed-meshheading:7783127-Models, Molecular,
pubmed-meshheading:7783127-Molecular Conformation,
pubmed-meshheading:7783127-Phenylalanine,
pubmed-meshheading:7783127-Propionic Acids,
pubmed-meshheading:7783127-Rats,
pubmed-meshheading:7783127-Receptors, N-Methyl-D-Aspartate,
pubmed-meshheading:7783127-Stereoisomerism,
pubmed-meshheading:7783127-Synaptosomes,
pubmed-meshheading:7783127-Tritium
|
| pubmed:year |
1995
|
| pubmed:articleTitle |
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.
|
| pubmed:affiliation |
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
|
| pubmed:publicationType |
Journal Article
|