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Discovery of a potent and selective TRPC3 antagonist with neuroprotective effects
Jiaxing Wang1, Sicheng Zhang1, Vijay K Boda1
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Abstract:
The TRPC3 protein plays a pivotal role in calcium signaling, influencing cell function. Aberrant TRPC3 expression is implicated in various pathologies, including cardiovascular diseases, tumors, and neurodegeneration. Despite its functional similarities with TRPC6 and TRPC7, TRPC3 exhibits distinct roles in disease contexts. Therefore, it is of paramount importance to develop a potent and selective TRPC3 antagonist with favorable drug-like properties. We employed extensive medicinal chemistry synthesis and structure-activity relationships (SARs) study. Thirty-one novel TRPC3 antagonists were designed and synthesized using the lead compound JW-65 as the scaffold. Compound 60a exhibits a 4-fold improvement in potency and displays exceptional selectivity. With favorable drug-like properties, this compound shows a heightened in vitro neuronal protective effect. Molecular modeling suggests possible modes of action between the TRPC3 protein and its antagonists. In summary, 60a holds significant promise for clinical development in conditions associated with TRPC3 dysregulation.
Insights
Researchers developed a novel TRPC3 antagonist, compound 60a, showing improved potency and selectivity for potential therapeutic use in diseases linked to TRPC3 protein dysfunction.
Area of Science:
- Pharmacology
- Molecular Biology
- Medicinal Chemistry
Background:
- TRPC3 protein is crucial for calcium signaling and cell function.
- Dysregulated TRPC3 expression is linked to cardiovascular diseases, tumors, and neurodegeneration.
- Selective TRPC3 antagonists are needed due to TRPC3's distinct disease roles compared to TRPC6/TRPC7.
Purpose of the Study:
- To design and synthesize novel TRPC3 antagonists.
- To identify a potent and selective TRPC3 antagonist with favorable drug-like properties.
- To evaluate the therapeutic potential of novel TRPC3 antagonists.
Main Methods:
- Medicinal chemistry synthesis and structure-activity relationship (SAR) studies.
- Design and synthesis of 31 novel TRPC3 antagonists based on the JW-65 scaffold.
- In vitro evaluation of antagonist potency, selectivity, and neuronal protective effects.
- Molecular modeling to elucidate potential mechanisms of action.
Main Results:
- Thirty-one novel TRPC3 antagonists were synthesized.
- Compound 60a demonstrated a 4-fold increase in potency and exceptional selectivity.
- Compound 60a exhibited favorable drug-like properties and enhanced in vitro neuronal protection.
- Molecular modeling provided insights into TRPC3-antagonist interactions.
Conclusions:
- Compound 60a is a promising TRPC3 antagonist with potential for clinical development.
- This compound may be beneficial for treating conditions associated with TRPC3 dysregulation.
- The developed antagonists offer new therapeutic avenues for TRPC3-related pathologies.
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