Pharmacological characterization and modeling of the binding sites of novel 1,3-bis(pyridinylethynyl)benzenes as metabotropic glutamate receptor 5-selective negative allosteric modulators.
Metabotropic glutamate receptor subtype 5 (mGluR5) is a potential drug target in neurological and psychiatric disorders, and subtype-selective allosteric modulators have attracted much attention as potential drug candidates. In this study, the binding sites of three novel 2-methyl-6-(phenylethynyl)pyridine (MPEP)-derived negative allosteric modulators, 2-, 3-, and 4-BisPEB, have been characterized. 2-, 3-, and 4-BisPEB are 1,3-bis(pyridinylethynyl)-benzenes and differ only by the position of the nitrogen atoms in the pyridine rings. Despite their high structural similarity, 2-BisPEB [1,3-bis(pyridin-2-ylethynyl)-benzene, nitrogen atoms in ortho positions], with an IC(50) value in the nanomolar range, is significantly more potent than the 3- and 4-pyridyl analogs. Mutational analysis, directed by a previously published mGluR5 homology model, was used to determine key residues for the ligand-receptor interactions that may explain the potency differences of 2-, 3-, and 4-BisPEB. Residues Ile651, Pro655, Tyr659, Asn747, Trp785, Phe788, Tyr792, Ser809, and Ala810 were found to have critical roles for the activity of one or more of the three BisPEBs and the reference compound MPEP. The mutagenesis data suggest that the higher potency of 2-BisPEB is due to hydrogen bonding to Ser809 because the S809A mutation made 2-BisPEB equipotent to 3- and 4-BisPEB (IC(50), 1-2.5 μM). The potency of MPEP was also greatly affected by S809A (52-fold), suggesting that a Ser809-mediated hydrogen bond is also a key interaction between MPEP and mGluR5. Potential binding modes of 2-, 3-, and 4-BisPEB obtained by molecular docking to the mGluR5 homology model provide a structural context for the reported major mutational effects.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Christina
C
Mølck
Kasper
K
Harpsøe
David E
DE
Gloriam
Rasmus P
RP
Clausen
Ulf
U
Madsen
Lars Ø
LØ
Pedersen
Hermogenes N
HN
Jimenez
Søren M
SM
Nielsen
Jesper M
JM
Mathiesen
Hans
H
Bräuner-Osborne
D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018678:Cholinergic Agents / Q000737:chemistry* / Q000494:pharmacology; D006224:Cricetinae; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D017354:Point Mutation; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000480:Alkynes; D001555:Benzene Derivatives; D018678:Cholinergic Agents; C578935:GRM5 protein, human; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D002118:Calcium