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The research activity of the NeuroDrugs Group at the Medicinal Chemistry Institute is focused on the design, synthesis, biological study and further optimization of structurally diverse chemical entities for treating neurological diseases. We are especially interested in developing innovative neurogenic and/or neuroprotective agents and photoswitchable neurodrugs, in the fields of the Regenerative Medicine and the Photopharmacology, respectively.

⇀  Regenerative Medicine is one of the most innovative therapeutic approaches for the treatment of different pathologies. Undoubtedly, it will be a mainstay of the future medicine, although nowadays there are still several obstacles to overcome, such as the development of therapies for the nervous system. Efficient regeneration of damaged tissues by an accident (e.g., trauma, stroke), by neurodegenerative diseases (e.g., Alzheimer, Parkinson, amyotrophic lateral sclerosis) or psychiatric conditions (e.g., mood disorders, anxiety, major depression) would be a great advance to achieve the definitive cure for these diseases. Indeed, the discovery of the existence of neural stem-cells niches in the adult human brain opens the door to the development of small molecules as restorative therapies for such pathologies. Our group is interested in contributing to the Regenerative Medicine by the discovery of new drugs able to promote neuro-regeneration by endogenous stimulation of the brain neurogenesis.

Targets involved in neurogenesis are huge and most of them remain to be determined. For that reason, we have focused initially our projects and resources on several targets with different degree of knowledge about their involvement in neurogenesis and axonal growth. We have chosen receptors of melatonin, serotonin, cannabinoids, and nicotine, as well as the Wnt/beta-catenin and the nuclear erythroid 2-related factor-antioxidant response elements (Nrf2-ARE) pathways as potential neurogenic targets. All of these pharmacological receptors are involved in the pathology of neurodegenerative and mental diseases and some of them may exert neuroprotective actions through antioxidant, anti-inflammatory and anti-excitotoxic properties.

⇀  Photopharmacology has undergone a rapid development in the past decade. New findings in areas as diverse as chemistry, biology, and pharmacy continue to provide new evidence for its therapeutic potential. Photopharmacology is defined as the use of drugs that can be selectively activated and/or deactivated with light irradiation at different wavelengths. The use of light grants fine-tuning in the control of drug delivery with high spatial and temporal resolution, such that can discriminate single cells. Drug photoactivation can be achieved from either outside the body, by the use of a light source, or inside by the use of activated fluorescent compounds. In addition, the current technology allows the use of optical fibres for the delivery of photonic excitation on specific tissues, with minimum invasiveness for lab animals and patients. Thus, photoswitchable drugs can be turned off and on upon light interaction, preventing systemic and environmental side effects of conventional medicines.

Our group is now involved in developing photoswitchable drugs acting on different types of ion channels, such as nicotinic acetylcholine receptors (nAChR) and voltage-gated potassium-selective (K_v) channels.

The research activity of the NeuroDrugs Group comprises three complementary areas:

1)      Rational design, synthesis, pharmacological evaluation and further optimization of innovative drugs for neurological diseases.We use computer-aided rational design to guide the generation of new families of multifunctional drugs capable of acting on different pharmacological targets (melatonin, serotonin, nicotine, and cannabinoid receptors, BACE-1, GSK-3beta, Nrf2, etc.)

2)      Creation and screening of an in-house chemical library composed of about 1000 products with privileged structures to act in the nervous system. As a result of ongoing work on neurodegenerative disease projects, the group has created a computerized collection of compounds with privileged structures to act in the nervous system and which has already produced very positive results. As a result of a screening campaign in oxidative stress cell models, two families of multifunctional mitochondrial neuroprotective drugs have been developed, which were first patented and then published in renowned scientific journals.

3)      Development of biological and pharmacological tools of special interest to our research lines, as in vitro / in silico methods to evaluate biological and drug-like properties (e.g., oral absorption and CNS penetration). Moreover, we develop fluorescent probes for labeling membrane receptors.