Exploring PDM-042: A Promising PDE10A Inhibitor for Schizophrenia Treatment in Rats

3 June 2024
A newly discovered inhibitor of phosphodiesterase 10A, referred to as PDM-042, has been found to exhibit strong inhibitory effects on both human and rat PDE10A, with an IC50 value below 1 nmol/L. This compound demonstrates a remarkable selectivity over 1000 times against other phosphodiesterases. Radiolabeled PDM-042, denoted as [3H]PDM-042, has displayed a high affinity for rat striatal membranes, with a Kd value of 8.5 nmol/L, and its binding can be displaced by PDM-042 and another PDE10A inhibitor, MP-10, in a concentration-dependent manner.

In animal studies, PDM-042 has demonstrated excellent penetration into the brain, with a striatum to plasma ratio of 6.3, an occupancy rate of 86.6% at a dosage of 3 mg/kg, and a favorable oral bioavailability of 33%. Behavioral tests on rats have shown that PDM-042 is capable of significantly reducing MK-801-induced hyperactivity at doses ranging from 0.1 to 0.3 mg/kg, without influencing spontaneous movement. Additionally, it has mitigated the conditioned avoidance response at doses between 0.3 to 1 mg/kg.

In terms of side effects, PDM-042 has shown minimal impact on catalepsy even at a higher dosage of 10 mg/kg, which is well above the effective dose for conditioned avoidance response. Moreover, unlike risperidone and olanzapine, which increase prolactin release and glucose levels respectively at doses near their therapeutic levels, PDM-042 has not affected these parameters up to a dosage of 3 mg/kg.

These findings suggest that PDM-042 is a potent and selective PDE10A inhibitor with good oral activity and brain penetration, making it a promising candidate for further research into the role of PDE10A and its potential therapeutic applications in treating schizophrenia.

How to Use Synapse Database to Search and Analyze Translational Medicine Data?

The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

图片包含 应用程序

描述已自动生成

Click on the image below to go directly to the Translational Medicine search interface.

图形用户界面, 文本, 应用程序, 电子邮件

描述已自动生成