# Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression

> **NIH NIH R44** · PRIMETIME LIFE SCIENCES, LLC · 2020 · $840,580

## Abstract

Depression is a common mental disorder, which can be chronic or recurrent, markedly tarnishing a
person’s ability to function in their normal life. People with a depression can feel empty, sad, helpless,
restless, hopeless, anxious, worthless, guilty, irritable, ashamed or suicidal. They may lose interest in
routine work or physical activities. They show appetite disorder, problems concentrating, remembering
details or making decisions. It has also been shown that healthy people may exhibit sub-clinical levels of
depressive symptoms. Because of their impact on the society and widespread prevalence, depressive
symptoms are a significant public health concern. Nearly 20% of the population, show depression-like
symptoms at some point in their lives. Currently, there are 350 million people worldwide and 16 million
people in the US affected by depression, and the scope of the population affected by depression is
gradually expanding. The estimated market for antidepressants was $14.51 billion and will grow to $16.8
billion by the year 2020. Despite recent advances in pathophysiological hypotheses such as alterations
in neuroplasticity, neurogenesis, and neuroimmunological regulation, current treatments lack rapid
clinical efficacy limiting the ability, for example, to bring instant relief needed with suicidal patients.
Therefore, there is a need for the rapid treatment of depression.
The adenosine signaling pathway activated by sleep deprivation has shown rapid benefits in preclinical
and clinical studies. In particular, sleep deprivation upregulates adenosine A1 receptors (A1R) in mice
and humans. Dr. Jacobson and his group have identified a compound MRS5474 as a potent small-
molecule A1R agonist with exceptional drug-like properties. It is metabolically stable, orally bioavailable
and has an excellent safety profile in mice.
Our collaborator, Dr. Biber, has shown that A1R knockout mice exhibit an increased depressive-like
behavior and were resistant to the antidepressant effects of sleep deprivation. In contrast, he
demonstrated that upregulation of A1R had pronounced acute and chronic resilience toward depressive-
like behavior in various tests. Furthermore, they also showed that increased expression of homer1a is a
final common pathway mediating the antidepressant effects of different antidepressant treatments
including the A1R agonist. The A1R agonist MRS5474 induced a rapid antidepressant effects in animal
models of transgenic mice with intraperitoneal (IP) administration.
In summary, MRS5474 has great potential to be a rapid, efficacious and safe antidepressant with a
unique mechanism of action. The expression of Homer1a and ERK1,2 will serve as biomarkers for
preclinical and clinical studies.
In this Fast-Track proposal, we will first establish that 1) MRS5474 has good BBB penetration
(Brain/Plasma ratio ≥ 1), 2) direct relationship between exposure of MRS5474 and effects on Homer1a
expression levels and ERK activity, 3) A1R antidepressant eff...

## Key facts

- **NIH application ID:** 9987705
- **Project number:** 5R44MH116741-03
- **Recipient organization:** PRIMETIME LIFE SCIENCES, LLC
- **Principal Investigator:** Janak K Padia
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $840,580
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987705

## Citation

> US National Institutes of Health, RePORTER application 9987705, Development of an adenosine A1 receptors agonist, MRS5474 for the treatment of chronic depression (5R44MH116741-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987705. Licensed CC0.

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