# Novel 5-HT7 Antagonists for the Treatment of Pruritus

> **NIH NIH R43** · PRAEVENTIX, LLC · 2022 · $275,544

## Abstract

Project Summary (Abstract)
Evidence supporting serotonin (5-HT) as a contributing factor to the severity of pruritus has been widely reported.
Elevated levels of 5-HT have been reported in patients with atopic dermatitis and chronic eczema, thus
supporting 5-HT as a contributing factor. Additionally, 5-HT invokes dose-dependent scratching when
administered via intradermal injection in rodents. Studies have demonstrated that 5-HT induces scratching
sensations by activating a subset of receptors. Substantial evidence supports a role of peripheral 5-HT7 receptors
in chronic itch via opening of the TRPA1 channel. Opening of the TRPA1 channel is reported to be required for
the manifestation of chronic pruritus. 5-HT7 is co-expressed with TRPA1 in a subset of primary afferent sensory
neurons that innervate the skin. When 5-HT7 was activated with either 5-HT or a highly selective 5-HT7 agonist
(LP-44) it triggers neuronal excitation via calcium flux thru the TRPA1 channel in a cyclic AMP dependent matter.
The involvement of 5-HT7 in pruritus was supported in vivo as intradermal administration of LP-44 into the cheek
of mice evoked significant scratching behavior that was attenuated via pharmacological blockade with a selective
5-HT7 antagonist (SB-269970). 5-HT and LP-44 induced scratching was also attenuated in either 5-HT7 or
TRPA1 knock-out mice. Additionally, 5-HT7 and TRPA1 knock-out mice displayed reduced scratching and skin
lesion severity in an atopic dermatitis model (MC903 induced) where 5-HT levels were significantly increased at
the affected site. This data suggests that a 5-HT7 antagonist could be useful for the treatment of pruritus. We
have chosen 6 highly potent, selective 5-HT7 antagonists that display peripherally restricted
pharmacokinetic (PK), good dermal penetration/permeability and safe preliminary ADMET profiles. We
hypothesize that our novel 5-HT7 antagonists will attenuate scratching in murine models of pruritus (MC903) and
provide a novel mechanism for treating pruritus. We will pursue a multipronged approach focused on identifying
novel lead compounds suitable for advanced in vivo efficacy studies.

## Key facts

- **NIH application ID:** 10547410
- **Project number:** 1R43AR081768-01
- **Recipient organization:** PRAEVENTIX, LLC
- **Principal Investigator:** Carlos A Barrero
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $275,544
- **Award type:** 1
- **Project period:** 2022-07-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547410

## Citation

> US National Institutes of Health, RePORTER application 10547410, Novel 5-HT7 Antagonists for the Treatment of Pruritus (1R43AR081768-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10547410. Licensed CC0.

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