G protein-coupled receptors (GPCR) are the largest family of membrane receptors targeted by commercial drugs. However, the proportion of approved small molecules targeting GPCRs has slowed down within the last years. In large part. this is due to adverse effects or lack of efficacy found in clinical trials, which can be attributed to a low selectivity or ubiquitous expression of receptors in non-targeted tissues, thus eliciting undesired actions. Therefore, the innovative strategies are necessary to distinctly define the spatial and temporal action of GPCR drugs in therapeutically relevant areas. Definitely, strategies based on photopharmacology are a highly promising to overcome these limitations of conventional drugs.
Photopharmacology is based in the use of light-regulated drugs to control receptor activation states and represents an opportunity to control a drug target activity with light, offering an unparalleled spatial and temporal precision. Indeed, driving the drug action through the use of light has demonstrated to allow for an accurate restriction of its effect to specific organs, tissues or even subcellular locations with strictly defined time applications. Additionally, diffusible photopharmacological tools can be used as conventional drugs in cells, tissues and alive animals without the need to genetically modify the biological system to light-control the GPCR activity. Our group has demonstrated extensive expertise in the development of photopharmacological tool compounds to study the activity of different GPCRs, including metabotropic glutamate, melatonin, adrenergic, adenosine and opioid receptors among other drug targets. In collaboration with different partners, the capacity of this drugs to switch GPCR activity on and off with light has been demonstrated both in vitro and in vivo and hold promise to become new drug candidates and, thus, be exploited to treat unmet clinical needs.
In the present communication, we present different photopharmacological strategies as safer therapeutic alternatives to important diseases. We have developed a series of antagonists of β2-adrenoceptors which are inactive but, upon topical ocular application, the visible light can switch exclusively the drugs located in the eye. Thus, these photoactivated drugs can bind the ocular β2-adrenoceptors and decrease the ocular hypertension in murine models of glaucoma. Alternatively, we have developed light-sensitive drugs to treat chronic pain, such as a photocaged version of morphine, which can be injected systemically and locally activated ion the spinal cord with local illumination using wireless μLED implanted in the epidural space. Such local and precise photo-activation induced analgesic activity, but prevented the manifestation of other opioid-related adverse effects, such as tolerance, constipation or withdrawal symptoms. Additionally, we are currently developing a photoswitchable compound targeting metabotropic glutamate receptor 5 as the blockade of mGlu5 with NAMs has been proposed as pain treatment by targeting over-excitatory glutamate in pain pathways. The feasibility of a non-opioid, adjustable, reversible and real-time analgesic drug holds great therapeutic potential as it can be systemically administered and locally activated. This would enable precise pain control in specific areas without affecting adjacent tissues or distant organs, thus avoiding side effects.
Poster
