Research Projects

Schizophrenia is a debilitating mental disorder that affects the patient's health, wellbeing, autonomy, and life satisfaction. The available antipsychotics are effective in treating the positive symptoms of schizophrenia; however, there is insufficient evidence to support their efficacy on the negative symptoms and cognitive impairment. Therefore, there is an urgent need to develop new therapies that address all the three symptomatic domains of schizophrenia. Several studies have reported the potential of PDE1B inhibitors to treat cognitive impairment in schizophrenia due to the expression of PDE1B in the direct pathway neurons. PDE10A inhibitors have generated much excitement as a potentially novel therapy for schizophrenia due to the expression of PDE10A in both direct and indirect pathway neurons. However, the main effects of PDE10A inhibitors are exerted through the indirect pathway; therefore, they resemble the D2-receptor antagonist and cause extrapyramidal side effects, resulting in the failure in clinical trials. A dual inhibitor of PDE1B and PDE10A may be well suited to treat the cognitive impairment along with the positive and negative symptoms related to the deficient D1-dopaminergic signalling and high D2-dopaminergic signalling that exists in schizophrenia. In our previous work, first ever dual inhibitor of phosphodiesterase (PDE) 1B and PDE10A, compound 2 [3-fluorophenyl) (2-methyl-2,3-dihydro-4H-benzo[b] [1,4] oxazin-4-yl) methanone], was identified as lead compound for schizophrenia drug development. Compound 2 showed efficacy in animal models of schizophrenia which warrants further development of this compound. Therefore, the design of potent dual inhibitors of PDE1B and PDE10A, by optimization of compound 2 is envisaged via this research proposal. The structure-activity relationship of compound 2 will be studied based on our previous work as well as by further docking and molecular dynamic simulations studies, followed by modifying the structure of the compound to design novel inhibitors. Structure-based approach, including molecular docking, molecular dynamics simulations, and binding free energy calculations, will be applied to evaluate the affinity and stability of the new compounds toward PDE1B and PDE10A. Then, the designed compounds will be synthesised, followed by evaluating their potency and selectivity for PDE1B and PDE10A in vitro. In addition, the toxic effects, the antipsychotic activity, and side effects of the inhibitors will be studied in animal model of schizophrenia. The successful completion of the proposed work expects to put forth potent, selective, dual inhibitors of PDE1B and PDE10A as potential drug candidates to treat cognitive symptoms of schizophrenia along with the positive and negative symptoms.