Benzopyran derivative penetrates the blood–brain barrier, eliminates synaptic deficiency and restores memory deficit in 5xFAD mice
Authors: Popugaeva E. A. , Zernov N. I. , Veselovsky A. V. , Poroikov V. V. , Melentieva D. M. , Bolshakova A. V. 
Published: May 2024

Alzheimer’s disease (AD) is a neurodegenerative disease that primarily affects older individuals and is characterized by gradual memory loss. Effective drug therapy for the disease is currently lacking. The clinical study findings of the medicinal properties of amyloid-binding antibodies demonstrate a multifaceted and intricate pathogenic mechanism of AD. Consequently, there is a crucial necessity for the exploration of novel molecular targets that can be subjected to pharmacological intervention to impede the disease progression.
The calcium hypothesis of AD posits that the pathogenesis of AD is rooted in the aberrant performance of calcium-permeable proteins that disrupt Ca2+ homeostasis. Such proteins include plasma membrane ion channels (NMDAR, AMPAR, and VGCC), intracellular ER ion channels (RyanR and IP3R), TRPC6-dependent store operated channels, and the mitochondrial pore-forming protein (mPTP). In support of the calcium hypothesis, the only pharmaceutical medication that offers temporary relief of AD symptoms is the memantine, an NMDAR blocker.
Synaptic loss in the brains of AD patients is associated with cognitive impairments. Drugs that reduce synaptic loss show promise as pharmacological agents. The transient receptor potential cation channel, subfamily C, member 6 (TRPC6), regulates excitatory synapse formation. Positive regulation of TRPC6 leads to increased synapse formation, enhances learning and memory in animal models. Therefore, TRPC6 channels constitute an attractive molecular target. We have previously demonstrated that TRPC6 channels regulate store-operated calcium entry (nSOCE) in hippocampal neurons [1]. TRPC6-dependent nSOCE is essential for support of neuronal spines and protection against amyloid toxicity in vitro. Research indicated that TRPC6 positive regulators can restore long-term potentiation deficits in brain slices obtained from AD transgenic mouse models. However, none of the TRPC6-targeting compounds tested in our study have successfully crossed the blood-brain barrier (BBB).
Recently, a novel selective TRPC6 agonist, 3-(3-,4-dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one (C20), was identified [2]. The aim of this study is to investigate the therapeutic profile of the newly discovered selective TRPC6 positive modulator. Our findings indicate that C20 binds to TRPC6 extracellularly at the agonist binding site. Additionally, C20 exhibits synaptoprotective properties in in vitro experiments and recovers synaptic plasticity in brain slices of aged 5xFAD mice. C20 effectively passes through the BBB without causing acute or chronic toxicity in dosages ranging from 10–100 mg/kg. In a 14-day treatment of intraperitoneal injections with a 10 mg/kg dosage of C20, hippocampus-dependent context and hippocampus-independent cued fear memory improved in 5xFAD mice [3]. Therefore, C20 is a promising TRPC6-specific compound that may aid in reducing cognitive decline.