A study published in the Journal of Medicinal Chemistry presents a new family of candidate compounds for the treatment of Alzheimer’s disease and pain, which have shown promising effects in animal models. Researchers of the University of Barcelona led a multidisciplinary team that designed, synthetized and pharmacologically validated these molecules that modulate a therapeutic target which has been little studied, the imidazoline I2 receptors, which are altered in many diseases without efficient pharmacological treatments. According to the researchers, the new compound has the “necessary characteristics to progress in pre-clinical phases and to be positioned as a potential anti-Alzheimer’s drug or analgesic with a novel mechanism of action”.
The new study is coordinated by Carmen Escolano, professor at the UB’s Faculty of Pharmacy and Food Sciences and member of the UB Institute of Biomedicine (IBUB). It includes the participation of Mercè Pallàs and Christian Griñán-Ferré, researchers at the UB Institute of Neurosciences (UBneuro) and the Networking Biomedical Research Centre on Neurodegenerative Diseases (CIBERNED), among other experts from the same faculty. Researchers from the Universitat Autònoma de Barcelona, the Institute of Materials Science of Barcelona (ICMAB-CSIC), the University of the Basque Country, the Networking Biomedical Research Centre on Mental Health (CIBERSAM) area, the University of Granada, the Complutense University of Madrid, the University of Santiago de Compostela, the University of the Balearic Islands, the MEDINA Foundation Center of Excellence in Research of Innovative Medicines of Andalusia, the University of Belgrade (Serbia) and the Katholieke Universiteit Leuven (Belgium) have also collaborated.

Improving biochemical markers without toxic effects

Imidazole I2 receptors are located in different organs and have been shown to be involved in multiple physiological processes (analgesia, inflammation, nervous system disorders, etc.). In fact, their levels are altered in neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and their modulation has been shown to have an impact on pain, so these receptors have been identified as potential drug targets. The new study is the result of a demanding medicinal chemistry process, including synthetic processes, pharmacological, computational and toxicity studies, which led the researchers to develop compounds with high affinity and selectivity towards imidazole I2 receptors.

These candidate compounds have been tested in preliminary studies in animal models of both neurodegenerative disease and pain, where they have been shown to be highly efficient and have no toxic effects. “A murine model of Alzheimer’s disease treated with one of the new compounds selected has shown an improvement in cognitive and biochemical markers of the disease”, says Carmen Escolano. “This compound has also shown analgesic properties in a murine model of pain, with no motor side effects”, she adds.
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These are molecules that are structurally different from those used so far to interact with these receptors. “Having molecules that are highly affine and selective for these receptors allows us to describe their pharmacological implication in diseases such as Alzheimer’s and pain and to present drugs that improve their treatment”, notes the researcher.​​​
A known action mechanism

Another important element of the research is that the compound has a novel mechanism of action, which has been validated by several previous studies. The researchers see these results as an advantage in the development of new therapeutic agents. “Describing novel action mechanisms allows proposing new molecules that, after undergoing improvement processes, can become, after years of research, new drugs to cure diseases that need therapeutic alternatives”, stresses Carmen Escolano. “The development of new tools such as those presented in this paper, which allow us to modulate therapeutic targets involved in certain diseases, is the gateway to these new drugs”.

In this sense, researchers are already working on the complete characterization of imidazole I2 receptors in order to modulate them in a “very effective and selective way, which will open the field to the development of new molecules for different therapeutic indications”, concludes the researcher.