Dual biased 5-HT_1A and 5-HT₇ receptor agonists activating the sigma-1 receptor in the search for an innovative selenium-based antidepressant and procognitive agent with rapid onset of action

The idea

Depression is not only about mood - it also affects how we think, remember, and adapt. Yet most antidepressants fail to improve these aspects. In this project, we explore whether precisely designed molecules can activate selected signaling routes within serotonin and sigma receptors to produce faster and broader therapeutic effects.

Our approach

We are developing a new group of selenoether derivatives of phenylpiperazine - small molecules designed to modulate 5-HT_1A, 5-HT₇, and σ₁ receptors. We will evaluate their receptor binding, functional selectivity, and neuroprotective properties to identify compounds with the most favorable profiles. Promising candidates will undergo behavioral testing to assess their effects on mood and cognition. To explore mechanisms of action, we plan to use techniques such as fiber photometry with FRET biosensors, allowing us to monitor receptor-dependent signaling in real time.

Why it matters

By combining medicinal chemistry, molecular and behavioral pharmacology with in vivo molecular imaging techniques, this project helps us understand how selective receptor signaling can shape mood and cognition. The results may support the development of antidepressant strategies that act faster and more precisely, with fewer side effects.

Grant number: 2024/53/B/NZ7/03768