Neurodegeneration and neuropathologies
“Genetics loads the gun and the environment pulls the trigger”
― Michael J. Fox at the Late Show with David Letterman, 2015
Schizophrenia and D2
Dopamine D2 receptor (D2R) is the main target of first (typical) and second (atypical) generation antipsychotic drugs used to treat different mental health conditions, such as bipolar disorders, mood instability and schizophrenia, among others. The so-called typical antipsychotic drugs treat positive schizophrenia symptoms (such as hallucination and delusions), although they induce concomitant on-target side-effects due to an excessive blockade of the D2R. On the other hand, the atypical antipsychotics are characterized by a reduction of these side effects, mostly due to their residence time (RT). In particular for this receptor, a short RT or lifetime (the residence time describes how long a ligand is bound to its target) for the drug may be crucial to avoid mechanism-based side effects (toxicity).
Therefore, our goal is to design new ligands for the D2R with modified RT. Specifically, we aim to shorten the ligands’ lifetime, since this was shown to correlate with a reduced toxicity for the D2R. First, we are going to reproduce the kinetics of the currently available antipsychotic drugs. Then this knowledge will be exploited to identify tailored modifications of the chemical structure of the drug to regulate its kinetic.
People involved
Prof. Dr. Giulia Rossetti
Group leader of Drug Design Hub for Digital Neuropharmacology
Prof. Dr. Paolo Carloni
Director
Collaborators
- Institute of Neurosciences and Medicine (INM)
- Nuklearchemie (INM-5)
Room 4011
Fundings
Helmholtz European Partnering Project with
Parkinson's and A2A
Parkinson’s disease belongs to the family of neurodegenerative disorders, in which the progressive damage of dopaminergic neurons in the substantia nigra leads to a drastic reduction in the dopamine concentration of the striatum. Bradykinesia, muscular rigidity, and tremor are only the most visible challenges of patients. The cause of Parkinson’s disease is still unknown, although participation of free radicals, oxidative stress, and environmental toxins is postulated. Drugs that increase the concentration of dopamine in the stratum like the dopamine precursor L-DOPA (L-3,4-dihydroxyphenylalanine) and dopaminergic receptor agonists, alleviate the symptoms, but suffer from poor long-term properties. Parkinson’s disease patients who are experiencing “wearing-off phenomenon” while taking L-DOPA alone, can be diminished by combining their treatment with A2a antagonists, which has shown to reduces the “off” time, and patients remain in the longer “on” phase with symptoms of non troublesome dyskinesia.
Finding novel potent and selective small molecule ligands through rational drug design is a challenging task for the adenosine receptors. One reason for this is the spatial similarity between different adenosine receptor subclasses, especially the A1 and A3 receptors (49% sequence similarity) and the A2a and A2b (59% similarity). Therefore, the spatial features responsible for the recognition of specific ligands are similar in between subclasses. This leads to an ambiguity in small molecular modulators of these receptors, as a molecule can affect the function of multiple subtypes, which decreases its selectivity. These challenges open the possibility to enhance the drug design pipeline for this class of receptors by comparing spatial differences in silico and virtually screening molecular databases for novel inhibitors of the A2a.
People involved
Dr. Rui Ribeiro
Visiting scientist
Prof. Alejandro Giorgetti
Associated member
Prof. Dr. Giulia Rossetti
Group leader of Drug Design Hub for Digital Neuropharmacology
Prof. Dr. Paolo Carloni
Director