Nowy inhibitor fosfodiesterazy 10A jako potencjalny lek w terapii schizofrenii : praca doktorska

Matłoka, Mikołaj

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Nowy inhibitor fosfodiesterazy 10A jako potencjalny lek w terapii schizofrenii : praca doktorska

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Title: Nowy inhibitor fosfodiesterazy 10A jako potencjalny lek w terapii schizofrenii : praca doktorska

Abstract:

Schizophrenia still remains a significant burden on patients, societies and healthcare systems. Current therapies focus mainly on alleviating only the positive symptoms, and, at the same time, cause numerous side effects. Furthermore, a large number of patients doesn’t respond to the treatment. Due to that there is a strong medical need to develop innovative drugs with a new mechanism of action. Cyclic nucleotides are an important secondary messenger dependent on the activation of G proteins that are hydrolysed by phosphodiesterases. Phosphodiesterase 10A (PDE10A) is selectively expressed in medium spiny neurons in the striatum where it affects the intensity and duration of signalling through the regulation of cAMP and cGMP concentration. As schizophrenia and many other psychiatric and neurological disorders are linked to striatum and disturbances of its circuits, the inhibition of PDE10A activity is considered as an potential therapeutic approach. The main aim of this study was to identify an innovative, low-molecular-weight PDE10A inhibitor and to characterize its pharmacokinetic and pharmacodynamic properties. The lead molecule CPL500036 was selected based on the results of screening assays. The identified compound was by highly active towards PDE10A and selective against another member of the phosphodiesterase family as determined by in vitro enzymatic assays. CPL500036 was shown to be metabolically stable and further studies have confirmed that it is characterized by high oral bioavailability and good penetration of the blood-brain barrier in rats. Additionally, the administration of CPL500036 led to increased phosphorylation of GluR1 in the rats’ striatum. In the second part of this thesis, a set of in vivo pharmacokinetic and pharmacodynamic experiments was performed in rats aiming at further characterisation of CPL500036. Intravenous and intragastric administrations allowed to determine the pharmacokinetic parameters confirming high bioavailability, dose-dependent exposure and good penetration into the brain. CPL500036 administration in rats resulted in an increase in the concentration of cyclic nucleotides and in the induction of expression of early response genes. Both effects were observed selectively in the striatum. In conclusion, a novel, innovative PDE10A inhibitor with promising pharmacological properties has been identified. Characteristics of CPL500036 allows for the continuation of preclinical and clinical development of the molecule as a new potential therapy in diseases related to the basal ganglia, including schizophrenia.