title: Potential Therapeutic Value of a Novel FAAH Inhibitor for the Treatment of Anxiety.
abstract: Anxiety disorders are among the most prevalent psychiatric diseases with high personal costs and a remarkable socio-economic burden. However, current treatment of anxiety is far from satisfactory. Novel pharmacological targets have emerged in the recent years, and attention has focused on the endocannabinoid (eCB) system, given the increasing evidence that supports its central role in emotion, coping with stress and anxiety. In the management of anxiety disorders, drug development strategies have left apart the direct activation of type-1 cannabinoid receptors to indirectly enhance eCB signalling through the inhibition of eCB deactivation, that is, the inhibition of the fatty acid amide hydrolase (FAAH) enzyme. In the present study, we provide evidence for the anxiolytic-like properties of a novel, potent and selective reversible inhibitor of FAAH, ST4070, orally administered to rodents. ST4070 (3 to 30 mg/kg per os) administered to CD1 male mice induced an increase of time spent in the exploration of the open arms of the elevated-plus maze. A partial reduction of anxiety-related behaviour by ST4070 was also obtained in Wistar male rats, which moderately intensified the time spent in the illuminated compartment of the light-dark box. ST4070 clearly inhibited FAAH activity and augmented the levels of two of its substrates, N-arachidonoylethanolamine (anandamide) and N-palmitoylethanolamine, in anxiety-relevant brain regions. Altogether, ST4070 offers a promising anxiolytic-like profile in preclinical studies, although further studies are warranted to clearly demonstrate its efficacy in the clinic management of anxiety disorders.
authors.affiliation: Section of Behavioural Neuroscience, Dept. Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Marco
authors.affiliation: Dept. Biomedical Sciences, Università degli Studi di Teramo, Teramo, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rapino
authors.affiliation: Sigma-Tau R&D, Pomezia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Caprioli
authors.affiliation: Sigma-Tau R&D, Pomezia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.affiliation: Section of Behavioural Neuroscience, Dept. Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Laviola
authors.affiliation: School of Medicine, Campus Bio-Medico University of Rome, Rome, Italy; Centro Europeo di Ricerca sul Cervello (CERC)/IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D014151:Anti-Anxiety Agents; D001713:Biphenyl Compounds; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D010880:Piperidines; D000099252:Fatty Acid Amide Hydrolases; C000607985:1-biphenyl-4-ylethenyl piperidine-1-carboxylate