We have shown that pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), blocks nicotine self-administration and prevents nicotine-induced reinstatement in squirrel monkeys, a model of human nicotine addiction and relapse to nicotine use. Based on these results, which point to FAAH as a promising molecular target for tobacco dependence, we propose to undertake a drug discovery program aimed at the optimization and preclinical development of FAAH inhibitors for smoking cessation. Our proposal has two primary goals:
Specific Aim 1 : Optimization of FAAH inhibitors and identification of a preclinical candidate for smoking cessation. We will conduct a lead optimization campaign starting from the compound URB694, a potent FAAH inhibitor previously identified in our laboratory. Compounds will be synthesized and tested in vitro and in vivo, and information collected will be used to design new molecules until a preclinical candidate with suitable efficacy and safety profile is selected.
Specific Aim 2 : Preclinical development of FAAH inhibitors for smoking cessation. We will (a) advance through preclinical development the candidate identified in Aim 1;(b) prepare and submit an Investigational New Drug (IND) application for the candidate with smoking cessation as therapeutic target;(c) seek private and/or public sponsors to support safety and proof-of-concept studies in humans after IND approval. To achieve these goals, we have assembled a multi-disciplinary consortium that unites scientific excellence with experience in industrial drug discovery and preclinical development. The team includes scientist and entrepreneur Daniele Piomelli (UCI), a leader in the field of FAAH inhibition;behavioral pharmacologist Steven Goldberg (NIDA-IRP), a pioneer in nicotine research;senior chemist Tiziano Bandiera (IIT);senior pharmacologist Angelo Reggiani (IIT);and preclinical development expert Edward Monaghan. Thus, our team combines the experience and skills required to translate an important research finding into a potential new treatment for tobacco dependence.

Public Health Relevance

Most cigarette smokers know that tobacco is a serious cause of disease, and would try to quit if effective treatments were available. Tobacco dependence is due to the addictive properties of nicotine. We discovered a new class of medications that reverse nicotine addiction in experimental animals, and propose now to lay the groundwork needed to translate this research finding into a clinically useful treatment for tobacco dependence.

National Institute of Health (NIH)
NIH Director’s Pioneer Award (NDPA) (DP1)
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Special Emphasis Panel (ZDA1)
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Shih, Ming L
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University of California Irvine
Schools of Medicine
United States
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De Simone, Alessio; Ruda, Gian Filippo; Albani, Clara et al. (2014) Applying a multitarget rational drug design strategy: the first set of modulators with potent and balanced activity toward dopamine D3 receptor and fatty acid amide hydrolase. Chem Commun (Camb) 50:4904-7
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Piomelli, Daniele; Sasso, Oscar (2014) Peripheral gating of pain signals by endogenous lipid mediators. Nat Neurosci 17:164-74
Sasso, Oscar; Moreno-Sanz, Guillermo; Martucci, Cataldo et al. (2013) Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain 154:350-60
Sasso, Oscar; Bertorelli, Rosalia; Bandiera, Tiziano et al. (2012) Peripheral FAAH inhibition causes profound antinociception and protects against indomethacin-induced gastric lesions. Pharmacol Res 65:553-63