Chronic treatment with novel brain-penetrating selective NOP receptor agonist MT-7716 reduces alcohol drinking and seeking in the rat

Neuropsychopharmacology. 2014 Oct;39(11):2601-10. doi: 10.1038/npp.2014.113. Epub 2014 Jun 27.

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 Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet.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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acenaphthenes / pharmacology*
  • Alcohol Deterrents / pharmacology*
  • Alcohol Drinking / drug therapy*
  • Alcohol Drinking / physiopathology
  • Animals
  • Benzimidazoles / pharmacology*
  • Choice Behavior / drug effects
  • Choice Behavior / physiology
  • Dose-Response Relationship, Drug
  • Drug-Seeking Behavior / drug effects*
  • Drug-Seeking Behavior / physiology
  • HEK293 Cells
  • Humans
  • Male
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Opioid Peptides / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Opioid / agonists*
  • Receptors, Opioid / metabolism
  • Stress, Psychological / complications
  • Substance Withdrawal Syndrome / drug therapy
  • Substance Withdrawal Syndrome / physiopathology

Substances

  • 2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N-methylacetamide
  • Acenaphthenes
  • Alcohol Deterrents
  • Benzimidazoles
  • Narcotic Antagonists
  • Opioid Peptides
  • Receptors, Opioid
  • Naltrexone
  • nociceptin
  • nociceptin receptor