Resumen de Deciphering the role of peripheral and central nervous system metabotropic glutamate receptors in neuropathic pain with photoactivable ligands
Pain is one of the main medical problems that in several cases results into a chronic disease with limited effective treatment, thus the discovery of new drugs to fight against constitutes a big challenge nowadays.
Metabotropic glutamate receptors (mGluRs) are widely distributed along the pain neuraxis and modulate pain transmission at different anatomical levels. Hence, subtype-selective mGlu receptors ligands are considered a promising candidate drugs for the treatment of acute, chronic and neuropathic pain. Accordingly, selective negative allosteric modulators (NAMs) of mGlu1 and mGlu5 receptors, and agonists or positive allosteric modulators (PAMs) of mGlu2 or mGlu4 receptors have consistently been shown to display analgesic activity in experimental animal models of chronic pain. However the systemic use may be limited by mechanism-related adverse effects. An effective strategy to overcome this limitation would consist of developing inactive photosensitive mGlu5, mGlu1 and mGlu4 receptors-based drugs, which may thereafter be activated by light administration with spatiotemporal control exclusively in the located area where pain takes place, or even in brain regions critically involved in pain control.
Two main optopharmacology approaches were used in this thesis for the photo delivering such as photoswitchable compounds (photoisomerisation) or caged compounds (photolysis).
On the one hand, photoswitchable compounds are molecules (normally azobenzenes) that coexist in two possible conformations (trans or cis) being the trans conformation the isomer thermodynamically stable. Moreover, these azo groups are bioisosteres of several groups such as amides, acetylenes or triazole. Interestingly, the addition of an azo group promotes the control of protein function, which had been demonstrated in a previous work with photoswitchable compounds as Alloswitch-1 or Optogluram. Unfortunately, their trans isomer provides the biological activity, meaning the compound is active in the stable disposition and we could just inactivate them upon irradiation. Due this reason, the needs to find a photoswitchable compound active in cis disposition are more interesting in a therapeutic point of view.
On the other hand, caged compounds consist in known drugs modifying by a single covalent bond, to mask the biological activity and release them selectively under light irradiation. The main issue presented by these compounds are a losing of control after irradiation.
Several photochromic compounds targeting the mentioned mGluRs were designed and synthesized in the present thesis, evaluating these compounds in several fields as photochemistry, pharmacology and even in in-vivo experiments.
