In this paper, we describe the synthesis of a series of
![](/images/gifchars/alpha.gif)
-substituted analogues of the potent
and selective group II metabotropic glutamate receptor (mGluR) agonist(1
S,1'
S,2'
S)-carboxycyclopropylglycine (
2, L-CCG 1). Incorporation of asubstituent on the amino acid carbonconverted the agonist
2 into an antagonist. All of thecompounds were prepared
and tested asa series of four isomers, i.e., two racemic diastereomers. Weexplored alkyl substitution, bothnormal
and terminally branched; phenylalkyl
and diphenylalkylsubstitution;
and a variety ofaromatic
and carbocyclic surrogates for phenyl. Affinity for groupII mGluRs was measuredusing [
3H]glutamic acid (Glu) binding in ratforebrain membranes. Antagonist activity wasconfirmed for these compounds by measuring their ability to antagonize(1
S,3
R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition offorskolin-stimulated cyclic-AMP in RGTcells transfected with human mGluR2
and mGluR3. We found thatwhile alkyl substitutionprovided no increase in affinity relative to
2, phenylethyl
and diphenylethyl substitution, asin
105 and 109, respectively, were quitebeneficial. The affinity of
109 was furtherenhancedwhen the two aromatic rings were joined by an oxygen or sulfur atom toform the tricyclicxanthylmethyl
and thioxanthylmethyl amino acids
113 and114, respectively. Amino acid
113,with an IC
50 of 0.010
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M in the[
3H]Glu binding assay, was 52-fold more potent than
2, whoseIC
50 was 0.47
![](/images/entities/mgr.gif)
M.