Synthesis and structure-activity relationship studies of novel 2-diarylethyl substituted (2-carboxycycloprop-1-yl)glycines as high-affinity group II metabotropic glutamate receptor ligands.
The major excitatory neurotransmitter in the central nervous system, (S)-glutamic acid , activates both ionotropic and metabotropic excitatory amino acid receptors. Its importance in connection to neurological and psychiatric disorders has directed great attention to the development of compounds that modulate the effects of this endogenous ligand. Whereas L-carboxycyclopropylglycine (L-CCG-1) is a potent agonist at, primarily, group II metabotropic glutamate receptors, alkylation of at the alpha-carbon notoriously result in group II mGluR antagonists, of which the most potent compound described so far, LY341495, displays IC(50) values of 23 and 10 nM at the group II receptor subtypes mGlu2 and mGlu3, respectively. In this study we synthesized a series of structural analogues of in which the xanthyl moiety is replaced by two substituted-phenyl groups. The pharmacological characterization shows that these novel compounds have very high affinity for group II mGluRs when tested as their racemates. The most potent analogues demonstrate K(i) values in the range of 5-12 nM, being thus comparable to LY341495.
Sørensen
Ulrik S
US
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, DC 1523 Indianapolis, IN 46285, USA.
Bleisch
Thomas J
TJ
Kingston
Anne E
AE
Wright
Rebecca A
RA
Johnson
Bryan G
BG
Schoepp
Darryle D
DD
Ornstein
Paul L
PL
D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003001:Cloning, Molecular; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014316:Tritium; D014966:Xanthenes / Q000737:chemistry* / Q000494:pharmacology*
D000596:Amino Acids; D001555:Benzene Derivatives; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; D014316:Tritium; D005998:Glycine