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Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2017

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

Résumé

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.

Dates et versions

hal-02066019 , version 1 (13-03-2019)

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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, 2017, 127, pp.567-576. ⟨10.1016/j.ejmech.2017.01.013⟩. ⟨hal-02066019⟩
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