title: Glutamate receptor ligands: synthesis, stereochemistry, and enantiopharmacology of methylated 2-aminoadipic acid analogs.
abstract: Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA) analogs, and the synthesis, stereochemistry, and enantiopharmacology of 3-methyl-AA (4a-d), 4-methyl-AA (5a-d), 5-methyl-AA (6a-d), and (E)-Delta(4)-5-methyl-AA (7a and 7b) are reported. The compounds were resolved using chiral HPLC and the configurational assignments of the enantiomers were based on X-ray crystallographic analyses, chemical correlation, and CD spectral analyses. The effects of the individual stereoisomers at ionotropic and metabotropic (S)-Glu receptors (iGluRs and mGluRs) were characterized. Compounds with S-configuration at the alpha-carbon generally showed mGluR2 agonist activity of similar or slightly lower potencies than (S)-AA [e.g., EC(50) = 76 microM for (2S,4S)-4-methyl-AA (5a) as compared to EC(50) = 35 microM for (S)-AA]. The position of the methyl substituent had a profound effect on the observed pharmacology, whereas the absolute stereochemistry at the methylated carbon atom had a very limited effect on pharmacology. Structure-activity relationships at iGluRs in the rat cortical wedge preparation showed a complex pattern, some compounds being NMDA receptor agonists [e.g., EC(50) =110 microM for (2S,5RS)-5-methyl-AA (6a,b)] and some compounds showing NMDA receptor antagonist effects [e.g., IC(50) = 300 microM for (2R,4S)-4-methyl-AA (5d)]. The two unsaturated analogs (S)- (7a) and (R)-(E)-Delta(4)-5-methyl-AA (7b) turned out to be a weak AMPA receptor agonist and a weak mixed NMDA/AMPA receptor antagonist, respectively.
authors.affiliation: Center for Drug Design and Transport, Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Copenhagen, Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Guldbrandt
authors.forename: Tommy N
authors.initials: TN
authors.lastname: Johansen
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Hans
authors.initials: H
authors.lastname: Bräuner-Osborne
authors.forename: Tine B
authors.initials: TB
authors.lastname: Stensbøl
authors.forename: Birgitte
authors.initials: B
authors.lastname: Nielsen
authors.forename: Rolf
authors.initials: R
authors.lastname: Karla
authors.forename: Flavio
authors.initials: F
authors.lastname: Santi
authors.forename: Povl
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: Ulf
authors.initials: U
authors.lastname: Madsen
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002942:Circular Dichroism; D006224:Cricetinae; D018360:Crystallography, X-Ray; D066298:In Vitro Techniques; D008024:Ligands; D008745:Methylation; D008958:Models, Molecular; D051381:Rats; D017470:Receptors, Glutamate / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D008024:Ligands; D017470:Receptors, Glutamate; D011994:Recombinant Proteins; D015074:2-Aminoadipic Acid