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J Med Chem. 2018 May 24;61(10):4436-4455. doi: 10.1021/acs.jmedchem.8b00109. Epub 2018 May 15.

Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders.

Author information

1
Department of Pharmaceutical Sciences , Università del Piemonte Orientale , Largo Donegani 2 , 28100 Novara , Italy.
2
Instituto de Biología Molecular y Celular , Universitas Miguel Hernandez , Av de la Universidad s/n , 03202 Elche , Spain.
3
AntalGenics, SL. Ed. Quorum III, Parque Científico UMH, Av de la Universidad s/n , 03202 Elche , Spain.

Abstract

Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.

PMID:
29722529
DOI:
10.1021/acs.jmedchem.8b00109
[Indexed for MEDLINE]

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