Abstract
Light-operated drugs constitute a major target in drug discovery, since they may provide spatiotemporal resolution for the treatment of complex diseases (i.e. chronic pain). JF-NP-26 is an inactive photocaged derivative of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulator raseglurant. Violet light illumination of JF-NP-26 induces a photochemical reaction prompting the active-drug's release, which effectively controls mGlu5 receptor activity both in ectopic expressing systems and in striatal primary neurons. Systemic administration in mice followed by local light-emitting diode (LED)-based illumination, either of the thalamus or the peripheral tissues, induced JF-NP-26-mediated light-dependent analgesia both in neuropathic and in acute/tonic inflammatory pain models. These data offer the first example of optical control of analgesia in vivo using a photocaged mGlu5 receptor negative allosteric modulator. This approach shows potential for precisely targeting, in time and space, endogenous receptors, which may allow a better management of difficult-to-treat disorders.
Highlights
Metabotropic glutamate receptors are widely distributed along the pain neuraxis and modulate pain transmission (Kolber, 2015) at different anatomical levels
We applied a caging strategy to generate a photocaged compound based on the chemical binding of the metabotropic glutamate type 5 (mGlu5) receptor negative allosteric modulators (NAMs), raseglurant (ADX-10059), to a coumarinyl phototrigger (Figure 1)
We synthesized a caged compound (JF-NP-26) that upon illumination would release raseglurant only in the areas of interest, avoiding potential systemic undesired effects associated to mGlu5 receptor functioning
Summary
Metabotropic glutamate (mGlu) receptors are widely distributed along the pain neuraxis and modulate pain transmission (Kolber, 2015) at different anatomical levels. Subtype-selective mGlu receptor ligands are considered as promising candidate drugs for the treatment of chronic pain. Selective negative allosteric modulators (NAMs) of mGlu or mGlu receptors, and agonists or positive allosteric modulators (PAMs) of mGlu or mGlu receptors have consistently been shown to display analgesic activity in experimental animal models of chronic pain (Montana and Gereau, 2011). MGlu receptor NAMs (i.e. raseglurant) are under development for the
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