Chiral Resolution, Pharmacological Characterization, and Receptor Docking of the Noncompetitive mGlu1 Receptor Antagonist (±)-2-Hydroxyimino- 1a,2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic Acid Ethyl Ester

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Abstract
Racemic CPCCOEt ((1aRS,7aRS)-2-hydroxyimino-1a,2-dihydro-1H-7-oxacyclopropa[b]naphthalene-7a-carboxylic acid ethyl ester, (±)-1) derivatives have been shown to be subtype-selective metabotropic glutamate (mGlu) 1 receptor antagonists (Annoura et al. Bioorg. Med. Chem. Lett.1996, 6, 763−766). The optical isomers of (±)-1 have been separated by chromatography on a chiral stationary phase. The absolute configuration at the C-1a and C-7a positions was determined using X-ray crystallography of an amide derivative with the methyl ester of l-phenylalanine (l-PheOMe) ((+)-6). In a phosphoinositol (PI) turnover assay at the cloned human mGlu1b receptor, ( − )-1 and the new amide derivatives ( − )-5 and ( − )-6, all of which have (1aS,7aS)-stereochemistry on the chromane ring system, showed IC50 values of 1.5, 0.43, and 0.93 μM, respectively. In contrast, (+)-1 and the new amide derivatives (+)-5 and (+)-6 were found to be inactive up to a concentration of 30 μM indicating a selectivity for the (−)-enantiomers of at least 70-fold. In a previous study (Litschig et al. Mol. Pharmacol.1999, 55, 453−461) we demonstrated using site-directed mutagenesis that the interaction site of (±)-1 is located in the transmembrane (TM) domain of hmGlu1b. To suggest a plausible binding mode of ( − )-1, we have built a molecular mechanics model of the putative seven TM domain of hmGlu1 based on the α-carbon template of the TM helices of rhodopsin. A receptor docking hypothesis suggests that the OH of T815 (TMVII) comes in close contact with the oxime OH of ( − )-1 and ( − )-5, whereas no such close interactions could be demonstrated by docking of (+)-1.

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