Structure-activity relationships for negative allosteric mGluR5 modulators

Birgitte H Kaae; Kasper Harpsøe; Trine Kvist; Jesper M Mathiesen; Christina Mølck; David E Gloriam; Hermogenes N Jimenez; Michelle A Uberti; Søren M Nielsen; Birgitte Nielsen; Hans Bräuner-Osborne; Per Sauerberg; Rasmus Prætorius Clausen; Ulf Madsen

doi:10.1002/cmdc.201100578

Structure-activity relationships for negative allosteric mGluR5 modulators

Birgitte H Kaae, Kasper Harpsøe, Trine Kvist, Jesper M Mathiesen, Christina Mølck, David E Gloriam, Hermogenes N Jimenez, Michelle A Uberti, Søren M Nielsen, Birgitte Nielsen, Hans Bräuner-Osborne, Per Sauerberg, Rasmus Prætorius Clausen, Ulf Madsen

15 Citations (Scopus)

Abstract

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.

Original language	English
Journal	ChemMedChem
Volume	7
Issue number	3
Pages (from-to)	440-451
ISSN	1860-7179
DOIs	https://doi.org/10.1002/cmdc.201100578
Publication status	Published - 5 Mar 2012

Keywords

Former Faculty of Pharmaceutical Sciences

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10.1002/cmdc.201100578

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title = "Structure-activity relationships for negative allosteric mGluR5 modulators",

abstract = "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.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Kaae, {Birgitte H} and Kasper Harps{\o}e and Trine Kvist and Mathiesen, {Jesper M} and Christina M{\o}lck and Gloriam, {David E} and Jimenez, {Hermogenes N} and Uberti, {Michelle A} and Nielsen, {S{\o}ren M} and Birgitte Nielsen and Hans Br{\"a}uner-Osborne and Per Sauerberg and Clausen, {Rasmus Pr{\ae}torius} and Ulf Madsen",

note = "Keywords: allosteric modulators; cross-coupling; mGluR5; molecular modeling; structure–activity relationships",

year = "2012",

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doi = "10.1002/cmdc.201100578",

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T1 - Structure-activity relationships for negative allosteric mGluR5 modulators

AU - Kaae, Birgitte H

AU - Harpsøe, Kasper

AU - Kvist, Trine

AU - Mathiesen, Jesper M

AU - Mølck, Christina

AU - Gloriam, David E

AU - Jimenez, Hermogenes N

AU - Uberti, Michelle A

AU - Nielsen, Søren M

AU - Nielsen, Birgitte

AU - Bräuner-Osborne, Hans

AU - Sauerberg, Per

AU - Clausen, Rasmus Prætorius

AU - Madsen, Ulf

N1 - Keywords: allosteric modulators; cross-coupling; mGluR5; molecular modeling; structure–activity relationships

PY - 2012/3/5

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N2 - 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.

AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

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DO - 10.1002/cmdc.201100578

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VL - 7

SP - 440

EP - 451

JO - ChemMedChem

JF - ChemMedChem

IS - 3

ER -

Structure-activity relationships for negative allosteric mGluR5 modulators

Abstract

Keywords

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