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

• Published in: Journal of medicinal chemistry Vol. 43; no. 23; pp. 4428 - 4436
• Main Authors: Ott, David, Floersheim, Philipp, Inderbitzin, Werner, Stoehr, Natacha, Francotte, Eric, Lecis, Gabrielle, Richert, Paul, Rihs, Grety, Flor, Peter Josef, Kuhn, Rainer, Gasparini, Fabrizio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.11.2000; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Biological and medical sciences; Chemistry, Medicinal; CHO Cells; Chromones - chemical synthesis; Chromones - chemistry; Chromones - pharmacology; Cricetinae; Crystallography, X-Ray; Excitatory Amino Acid Antagonists - chemical synthesis; Excitatory Amino Acid Antagonists - chemistry; Excitatory Amino Acid Antagonists - pharmacology; Glutamatergic system (aspartate and other excitatory aminoacids); Hydrolysis; Inositol Phosphates - metabolism; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - chemistry; Science & Technology; Stereoisomerism; Structure-Activity Relationship; POTENT; METABOTROPIC GLUTAMATE RECEPTORS; LY367385; EXPRESSION; BINDING; Stereoisomer; Oxime; Glutamate receptor; Tricyclic compound; Cetoxime; Oxygen heterocycle; In vitro; Modeling; Biological activity; Dose activity relation; Metabotropic receptor; Absolute configuration; Molecular model; Aromatic compound; Antagonist; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0009944

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.