Structure-Activity Relationships for Negative Allosteric mGluR5 Modulators

被引：15

作者：

Kaae, Birgitte H. ^{[1
,2
]}

Harpsoe, Kasper ^{[1
]}

Kvist, Trine ^{[1
]}

Mathiesen, Jesper M. ^{[1
]}

Molck, Christina ^{[1
]}

Gloriam, David ^{[1
]}

Jimenez, Hermogenes N. ^{[3
]}

Uberti, Michelle A. ^{[3
]}

Nielsen, Soren M. ^{[1
,4
]}

Nielsen, Birgitte

Brauner-Osborne, Hans ^{[1
]}

Sauerberg, Per ^{[5
]}

Clausen, Rasmus P. ^{[1
]}

Madsen, Ulf ^{[1
]}

机构：

[1] Univ Copenhagen, Dept Mol Drug Res, Fac Pharmaceut Sci, DK-2100 Copenhagen, Denmark

[2] Radiometer Med Aps, Radiometer Innovat, DK-2700 Bronshoj, Denmark

[3] Lundbeck Res USA, Glutamate Biol ST 1, Paramus, NJ 07652 USA

[4] H Lundbeck & Co AS, Mol Pharmacol, DK-2500 Valby, Denmark

[5] Novo Nordisk AS, Diabet Prot & Peptide Chem, DK-2760 Malov, Denmark

来源：

CHEMMEDCHEM | 2012年 / 7卷 / 03期

关键词：

allosteric modulators; cross-coupling; mGluR5; molecular modeling; structure-activity relationships; PROTEIN-COUPLED RECEPTORS; METABOTROPIC GLUTAMATE RECEPTORS; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; BINDING POCKETS; ANTAGONIST; EXPRESSION; SUBSET; FAMILY; IDENTIFICATION;

D O I：

10.1002/cmdc.201100578

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of compounds based on the mGluR5-selective ligand 2-methyl-6-(phenylethynyl)pyridine (MPEP) were designed and synthesized. The compounds were found to be either structural analogues of MPEP, substituted monomers, or dimeric analogues. All compounds retained mGluR5 selectivity with only weak or no activity at other mGluRs or iGluRs. The substituted analogue, 1,3-bis(pyridin-2-ylethynyl)benzene (19), is a potent negative modulator at mGluR5, whereas all other compounds lost potency relative to MPEP and showed that activity is highly dependent on the position of the nitrogen atom in the pyridine moieties. A homology modeling and ligand docking study was used to understand the binding mode and the observed selectivity of compound 19.

引用

页码：440 / 451

页数：12

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