2-SUBSTITUTED MINO-2-((1SR,2SR)-2-CARBOXYCYCLOPROP-1-YL)GLYCINES AS POTENT AND SELECTIVE ANTAGONISTS OF GROUP-II METABOTROPIC GLUTAMATE RECEPTORS - 1 - EFFECTS OF ALKYL, ARYLALKYL, AND DIARYLALKYL SUBSTITUTION

In this paper, we describe the synthesis of a series of a-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxy-cyclopropylglycine (2, L -CCG 1). Incorporation of a substituent on the amino acid carbon conve rted the agonist 2 into antagonist. Ail of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereome rs. We explored alkyl substitution, both normal and terminally branche d; phenylalkyl and diphenylalkyl substitution; and a variety of aromat ic and carbocyclic surrogates for phenyl. Affinity for group II mGluRs was measured using [H-3]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by me asuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-di carboxylic acid-induced inhibition of forskolin-stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. We found that w hile alkyl substitution provided no increase in affinity relative to 2 , phenylethyl and diphenylethyl substitution, as in 105 and 109, respe ctively, were quite beneficial, The affinity of 109 was further enhanc ed when the two aromatic rings were joined by an oxygen or sulfur atom to form the tricyclic xanthylmethyl and thioxanthylmethyl amino acids 113 and 114, respectively. Amino acid 113, with an IC50 of 0.10 mu M in the [H-3]Glu binding assay, was 52-fold more patent than 2, whose I C50 was 0.47 mu M.