Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu 5 negative allosteric modulation

Abstract : Modulation of metabotropic glutamate receptor 5 (mGlu5) with partial allosteric antagonists has received increased interest due to their favourable in vivo activity profiles compared to the unfavourable side-effects of full inverse agonists. Here we report on a series of bispyridine benzene derivatives with a functional molecular switch affecting antagonistic efficacy, shifting from inverse agonism to partial antagonism with only a single change in the substitution pattern of the benzene ring. These efficacy changes are explained through computational docking, revealing two different receptor conformations of different energetic stability and different positional isomer binding preferences.
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https://hal.umontpellier.fr/hal-02066019
Contributeur : Sandrine Beraud <>
Soumis le : mercredi 13 mars 2019 - 10:13:13
Dernière modification le : mardi 28 mai 2019 - 14:12:02

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Xavier Gómez-Santacana, James Dalton, Xavier Rovira, Jean Philippe Pin, Cyril Goudet, et al.. Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu 5 negative allosteric modulation. European Journal of Medicinal Chemistry, Elsevier, 2017, 127, pp.567-576. ⟨10.1016/j.ejmech.2017.01.013⟩. ⟨hal-02066019⟩

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