PDE1B and PDE10A as novel targets for schizophrenia: from molecular design and synthesis to therapeutic promise

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 management of schizophrenia. Recent advancements in structural and synthetic methodologies have significantly facilitated the design of small-molecule PDE1B and PDE10A inhibitors. Among these, ITI-214 (PDE1 inhibitors) and MK-8189 and EVP-6308 (PDE10A inhibitors) have proceeded to clinical trials, demonstrating promising therapeutic agents. Furthermore, dual PDE1B/10A inhibitors remain underexplored, with only compound 2 undergoing limited preclinical evaluation for its pharmacological efficacy and safety. Studies published between 2014 and 2025 were retrieved from the PubMed, Web of Science, and Scopus databases, highlighting advances in PDE1B and PDE10A inhibitors. This review provides a detailed overview of the structural and synthetic strategies employed in developing PDE1B, PDE10A, and dual PDE1/10 inhibitors, with a focus on their binding sites and structure-activity relationships (SARs). By addressing the limitations of current candidates and emphasizing the need for dual inhibitors, this review aims to guide future research efforts toward the discovery of more selective, potent, and clinically viable PDE1B and PDE10A inhibitors for schizophrenia.