PDE1B and PDE10A as novel targets for schizophrenia: from molecular design and synthesis to therapeutic promise
Jaya Rautela, Anand Gaurav, Veeranoot Nissapatorn, Chung Keat Tan, Ana Paula Girol, Maria De Lourdes Pereira, Vannajan Sanghiran Lee
TL;DR
This paper explores PDE1B and PDE10A as new targets for schizophrenia treatment, focusing on their role in dopamine signaling and the development of inhibitors to manage symptoms.
Contribution
The paper highlights recent advancements in designing PDE1B and PDE10A inhibitors and emphasizes the potential of dual inhibitors for schizophrenia treatment.
Findings
PDE1B inhibition enhances D1-receptor signaling, potentially improving negative symptoms and cognitive deficits in schizophrenia.
PDE10A inhibition modulates D2-receptor activity, which may alleviate positive symptoms of schizophrenia.
Dual PDE1B/10A inhibitors remain underexplored but show promise for comprehensive symptom management.
Abstract
Phosphodiesterase 1B (PDE1B) and phosphodiesterase 10A (PDE10A), members of the phosphodiesterase superfamily, are responsible for cyclic nucleotide hydrolysis, thereby regulating key intracellular signaling pathways such as cAMP response element-binding protein (CREB) activation and brain-derived neurotrophic factor (BDNF) gene transcription. Both enzymes are predominantly expressed in the brain and co-localize with dopamine receptors, positioning them as potential targets for addressing schizophrenia, a disorder characterized by dopamine system dysfunction. PDE1B inhibition enhances D1-receptor signaling, ameliorating negative symptoms and cognitive deficits, while PDE10A inhibition modulates D2-receptor activity, potentially alleviating positive symptoms. Together, these mechanisms suggest that targeting PDE1B and PDE10A could offer an innovative avenue for the comprehensive…
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Taxonomy
TopicsPhosphodiesterase function and regulation · Protein Kinase Regulation and GTPase Signaling · Histone Deacetylase Inhibitors Research