Novel 5-HT7 Antagonists for the Treatment of Pruritus

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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.