Researchers of the Neuropharmacology and Pain Research Group of the Bellvitge Biomedical Research Institute (IDIBELL), the University of Barcelona (UB) and ESTEVE, have developed a technology that enables to determine drugs’ analgesic potential before being tested in animal models. The finding saves time and money in the research on new effective pain treatments.
Traditionally in the development of analgesic drugs, the effectiveness of these molecules has been proved by using pain animal models, a hard, expensive and unclear process from a pharmacological point of view. Therefore, the great challenge is to develop more effective methodologies. Francisco Ciruela, senior lecturer of the Department of Pathology and Experimental Therapy at UB and researcher of the Neuropharmacology and Pain Research Group, explains: “We are talking about thousands of drugs; so, before testing them in preclinical pain models, that is, animal models, it will be useful to do a screening of the activity of these molecules in order to separate those that have greater antinociceptive potential".
The study led by Ciruela describes a new technology to determine the analgesic activity of drugs before being tested in animal models. “We have developed a Receptor Fluorescence Resonance Energy Transfer (FRET) based biosensor that allow us to classify in a simple system (cells in culture) ligands in sigma-1 receptor into agonists and antagonists”, details the researcher.
The experiments carried out by ESTEVE and the research group led by Dr Ciruela (IDEBELL-UB) with known drugs established a direct correlation between the biosensor FRET signal in response to these drugs and their analgesic effect in a pain animal model. Results show that, whereas sigma-1 agonists reduce FRET signal and have low analgesic effects, sigma-1 antagonists increase FRET signal and have high analgesic effects in pain animal models.
“Thanks to this well-defined pattern —explains Dr Ciruela—, we can predict the analgesic behaviour of a molecule”. Therefore, if FRET signal is reduced —that is, if it is an agonist—, it won’t have analgesic effects on the pain animal model; however, if FRET signal is increased —in other words, if it is an antagonist—, it will have maximum analgesic effects and, therefore, it will be a suitable candidate to be tested in vivo.
The researcher points out that the new technology has already been patented, and “although is too early to get the most of it —because FRET measures are now done one drug by one—, it is expected that it will be soon applied in an extensive way to the development of analgesic antagonists sigma-1 receptor”, highlights Ciruela. Therefore, the system will be robotized in order to develop a tool technically known as ‘high-throughput screening’ (HTS), in other words, a method to test many medicines in a quick and effective manner.
Analgesia: a subject area with many medical needs
There are two main groups of medicines in pain pharmacology: non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Each type has different action mechanisms with an ‘analgesic ceiling’ and different side effects. Whereas NSAIDs (for instance, ibuprofen) have a low-moderate analgesic potential and non-serious side effects, opioids (for instance, morphine) have high analgesic potential and serious side effects. So, there is an important analgesic gap, not only to present a risk-benefit favourable to treat moderate and severe pain, but also in the approach to pain treatment, a field in which medicines are not usually effective (for instance, in neuropathic pain).
ESTEVE focuses part of its R&D on active molecules for the treatment of neuropathic pain in patients receiving opioids. The main goal is to improve effectiveness, tolerance and safety and reduce side effects’ frequency of this group of drugs. In this sense, to block sigma-1 receptor with specific antagonists constitutes a new mechanism of action for pain in a field that needs new treatments. Therefore, besides the selective sigma-1 receptor antagonist, E-52862, which is now in a phase II clinical trial, ESTEVE has a number of molecules with potential activity on this receptor.
Gómez Soler, M.; Fernández Dueñas, V.; Portillo Salido, E.; Pérez, P.; Zamanillo, D.; Vela, J. M.; Burgueño, J., and Ciruela, F. "Predicting the antinociceptive efficacy of σ1 receptor ligands by a novel receptor fluorescence resonance energy transfer (FRET) based biosensor". Journal of Medicinal Chemistry, 2014, 57 (1), pp. 238-242.