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)
National Institute on Drug Abuse (NIDA)
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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Wang, W; Cox, B M; Jia, Y et al. (2018) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23:1798-1806
Khurana, Leepakshi; Mackie, Ken; Piomelli, Daniele et al. (2017) Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 124:3-12
Lim, James; Igarashi, Miki; Jung, Kwang-Mook et al. (2016) Endocannabinoid Modulation of Predator Stress-Induced Long-Term Anxiety in Rats. Neuropsychopharmacology 41:1329-39
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
Jung, Kwang-Mook; Piomelli, Daniele (2016) Assay of Monoacylglycerol Lipase Activity. Methods Mol Biol 1412:157-68
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
Scalvini, Laura; Piomelli, Daniele; Mor, Marco (2016) Monoglyceride lipase: Structure and inhibitors. Chem Phys Lipids 197:13-24
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
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
Sasso, Oscar; Wagner, Karen; Morisseau, Christophe et al. (2015) Peripheral FAAH and soluble epoxide hydrolase inhibitors are synergistically antinociceptive. Pharmacol Res 97:7-15

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