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.
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.
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|Sasso, Oscar; Pontis, Silvia; Armirotti, Andrea et al. (2016) Endogenous N-acyl taurines regulate skin wound healing. Proc Natl Acad Sci U S A 113:E4397-406|
|Scalvini, Laura; Piomelli, Daniele; Mor, Marco (2016) Monoglyceride lipase: Structure and inhibitors. Chem Phys Lipids 197:13-24|
|Panlilio, Leigh V; Thorndike, Eric B; Nikas, Spyros P et al. (2016) Effects of fatty acid amide hydrolase (FAAH) inhibitors on working memory in rats. Psychopharmacology (Berl) 233:1879-88|
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|Dotsey, Emmanuel Y; Jung, Kwang-Mook; Basit, Abdul et al. (2015) Peroxide-Dependent MGL Sulfenylation Regulates 2-AG-Mediated Endocannabinoid Signaling in Brain Neurons. Chem Biol 22:619-28|
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|Colombano, Giampiero; Albani, Clara; Ottonello, Giuliana et al. (2015) O-(triazolyl)methyl carbamates as a novel and potent class of fatty acid amide hydrolase (FAAH) inhibitors. ChemMedChem 10:380-95|
|Piomelli, Daniele; Hohmann, Andrea G; Seybold, Virginia et al. (2014) A lipid gate for the peripheral control of pain. J Neurosci 34:15184-91|
|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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