Positional isomers of bispyridine benzene derivatives induce efficacy changes on mGlu5 negative allosteric modulation

Abstract

Modulation of metabotropic glutamate receptor 5 (mGlu) 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.

Synthesis toward Bivalent Ligands for the Dopamine D2 and Metabotropic Glutamate 5 Receptors

“…Furthermore, as the original crystal structure of mGluR5 has no clear entrance or exit for NAMs because of its tightly closed extracellular loops and TMD, a modified conformation of the receptor was deemed necessary to correctly bind a bivalent compound. Such a conformation has been observed previously, first with a Monte Carlo sampling technique employed for the purposes of docking photosensitive and long linear mGluR5 NAMs, and second during molecular dynamics (MD) simulations of mGluR5 with bound NAM . In summary, this alternative mGluR5 conformation is in an inactive state and similar to the original mGluR5 crystal structure but undergoes a partial separation of the extracellular ends of TM5 and TM6, which are highly flexible .…”

Photopharmacology of G ‐Protein‐Coupled Receptors

“…In this method, during cell lysis it is used a buffer implemented with fluorescently labelled IP or cAMP with a FRET acceptor and an IP-or cAMP-recognising antibody labelled with a lanthanide cryptate/chelate. A competition between labelled and the endogenously produced IP or cAMP can be analysed by time-resolved FRET signal after incubation of the cells using different light conditions [6,7,25,33,[46][47][48][49][64][65][66] . The main limitation of this method is that photoswitches and photocages may interfere or quench the FRET signal between donor and acceptor molecules.…”

Reversible, Spatial and Temporal Control over Protein Activity Using Light

“…Recently, several in vivo studies of photopharmacological agents have been reported, mainly for neurological targets, such as restoring the visual function of the blind retina [51], and metabotropic glutamate receptors [40,52]. An impressive example of an in vivo-tested bioactive molecule with photo-controlled activity was reported by the groups of Gorostiza and Llebaria, targeting metabotropic glutamate receptor 5 [40,49,[53][54][55], which is a potential target for the treatment of anxiety, depression, and schizophrenia [56,57]. Inspired by negative allosteric modulator VU0414374, compound 3 was designed (Figure 3C) and tested in an in vivo system using hybrid optic and fluid cannulas that were implanted in the amygdala of persistent inflammatory pain mouse model.…”