title: Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat.
abstract: Since its discovery, the nociceptin/orphanin FQ (N/OFQ)-NOP receptor system has been extensively investigated as a promising target to treat alcoholism. Encouraging results obtained with the endogenous ligand N/OFQ stimulated research towards the development of novel brain-penetrating NOP receptor agonists with a pharmacological and toxicological profile compatible with clinical development. Here we describe the biochemical and alcohol-related behavioral effects of the novel NOP receptor agonist MT-7716. MT-7716 has high affinity for human NOP receptors expressed in HEK293 cells with a Ki value of 0.21 nM. MT-7716 concentration-dependently stimulated GTPγ(35)S binding with an EC50 value of 0.30 nM and its efficacy was similar to N/OFQ, suggesting that MT7716 is a full agonist at NOP receptors. In the two bottle choice test MT-7716 (0, 0.3, 1, and 3 mg/kg, bid) given orally for 14 days dose-dependently decreased voluntary alcohol intake in Marchigian Sardinian rats. The effect became gradually stronger following repeated administration, and was still significant 1 week after discontinuation of the drug. Oral naltrexone (30 mg/kg, bid) for 14 days also reduced ethanol intake; however, the effect decreased over the treatment period and rapidly disappeared when drug treatment was discontinued. MT-7716 is also effective for preventing reinstatement caused by both ethanol-associated environmental stimuli and stress. Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet. MT-7716 significantly attenuated somatic alcohol withdrawal symptoms. Together these findings indicate that MT-7716 is a promising candidate for alcoholism treatment remaining effective with chronic administration.
authors.affiliation: Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.affiliation: Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Stopponi
authors.affiliation: Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy.
authors.forename: Daina
authors.initials: D
authors.lastname: Economidou
authors.affiliation: Department II (CNS), Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuriyama
authors.affiliation: Department II (CNS), Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Laboratory of Clinical and Translational Studies, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.affiliation: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
authors.affiliation: Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Friedbert
authors.initials: F
authors.lastname: Weiss
authors.affiliation: Department II (CNS), Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Teshima
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000427:Alcohol Deterrents / Q000494:pharmacology*; D000428:Alcohol Drinking / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000073:Acenaphthenes; D000427:Alcohol Deterrents; D001562:Benzimidazoles; D009271:Naltrexone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000598520:2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N-methylacetamide