title: A novel delta opioid receptor antagonist, SoRI-9409, produces a selective and long-lasting decrease in ethanol consumption in heavy-drinking rats.
abstract: BACKGROUND
  Naltrexone, a compound with high affinity for the mu opioid receptor (MOP-R) reduces alcohol consumption. SoRI-9409 is a derivative of naltrexone that has highest affinity at delta opioid receptors (DOP-Rs). We have investigated the effects of SoRI-9409 on ethanol consumption to determine the consequences of altering the naltrexone compound to a form with increased efficacy at DOP-Rs.
  
  
  METHODS
  Effects of the opioid receptor antagonists, SoRI-9409 (0-30 mg/kg, IP), naltrexone (0-30 mg/kg, IP), or naltrindole (0-10 mg/kg, IP) on ethanol consumption was measured in high- and low-ethanol-consuming rats with two different drinking paradigms. SoRI-9409-, naltrexone-, and naltrindole-mediated inhibition of DOP-R-stimulated [(35)S]GTP gamma S binding was measured in brain membranes prepared from high-ethanol-consuming rats. The effects of SoRI-9409 on morphine-mediated analgesia, conditioned place preference, and anxiety were also examined.
  
  
  RESULTS
  In high- but not low-ethanol-consuming animals, SoRI-9409 is threefold more effective and selective at reducing ethanol consumption when compared with naltrexone or naltrindole for up to 24 hours. SoRI-9409 administered daily for 28 days continuously reduced ethanol consumption, and when the administration of SoRI-9409 was terminated, the amount of ethanol consumed remained lower compared with vehicle-treated animals. Furthermore, SoRI-9409 inhibits DOP-R-stimulated [(35)S]GTP gamma S binding in brain membranes of high-ethanol-consuming rats.
  
  
  CONCLUSIONS
  SoRI-9409 causes selective and long-lasting reductions of ethanol consumption. This suggests that compounds that have high affinity for DOP-Rs such as SoRI-9409 might be promising candidates for development as a novel therapeutic for the treatment of alcoholism.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California 94608, USA.
authors.forename: Carsten K
authors.initials: CK
authors.lastname: Nielsen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Simms
authors.forename: Haley B
authors.initials: HB
authors.lastname: Pierson
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Surendra K
authors.initials: SK
authors.lastname: Saini
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Ananthan
authors.forename: Selena E
authors.initials: SE
authors.lastname: Bartlett
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000648:ultrastructure; D002755:Choice Behavior / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage; D005518:Food Preferences / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D008297:Male; D009022:Morphine Derivatives / Q000627:therapeutic use*; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D009294:Narcotics / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D013395:Sucrose / Q000008:administration & dosage
chemical_list: D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D017465:Receptors, Opioid, delta; C425887:SoRI 9409; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000431:Ethanol; D013395:Sucrose
references.citation: Alcohol Clin Exp Res. 2008 Mar;32(3):498-504
references.pmid: 18241321
references.citation: Am J Psychiatry. 1985 Sep;142(9):1081-4
references.pmid: 2992300
references.citation: J Pharmacol Exp Ther. 2000 Jun;293(3):1002-8
references.pmid: 10869404
references.citation: Neuropsychopharmacology. 2002 Sep;27(3):391-9
references.pmid: 12225696
references.citation: Arch Gen Psychiatry. 1992 Nov;49(11):876-80
references.pmid: 1345133
references.citation: Neuroreport. 1998 Jul 13;9(10):2265-7
references.pmid: 9694212
references.citation: Drug Alcohol Depend. 1981 Aug;8(1):37-41
references.pmid: 7297411
references.citation: Psychopharmacology (Berl). 1991;103(4):467-72
references.pmid: 1648247
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12518-23
references.pmid: 17626178
references.citation: Psychopharmacology (Berl). 2002 Feb;160(1):19-29
references.pmid: 11862370
references.citation: Alcohol Clin Exp Res. 2005 May;29(5):730-8
references.pmid: 15897716
references.citation: NIDA Res Monogr. 1986;67:66-72
references.pmid: 3092099
references.citation: Psychopharmacology (Berl). 1995 Jul;120(2):177-85
references.pmid: 7480550
references.citation: Nat Genet. 2000 Jun;25(2):195-200
references.pmid: 10835636
references.citation: Brain Res. 1988 Sep 6;459(2):275-81
references.pmid: 2902901
references.citation: Pharmacol Biochem Behav. 1995 Sep;52(1):153-9
references.pmid: 7501658
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2002 Apr;365(4):296-302
references.pmid: 11919654
references.citation: Alcohol Clin Exp Res. 1996 May;20(3):584-8
references.pmid: 8727259
references.citation: J Med Chem. 1999 Sep 9;42(18):3527-38
references.pmid: 10479286
references.citation: Psychopharmacologia. 1973;29(3):203-10
references.pmid: 4702273
references.citation: Psychopharmacology (Berl). 2000 Dec;153(1):93-102
references.pmid: 11255932
references.citation: JAMA. 2006 May 3;295(17):2003-17
references.pmid: 16670409
references.citation: Alcohol. 1984 Jan-Feb;1(1):33-7
references.pmid: 6543609
references.citation: Pharmacol Biochem Behav. 1983 Feb;18(2):225-9
references.pmid: 6835979
references.citation: Addict Biol. 2006 Sep;11(3-4):397-403
references.pmid: 16961767
references.citation: Psychopharmacology (Berl). 2005 Nov;182(3):384-92
references.pmid: 16001119
references.citation: Drug Metab Dispos. 1976 May-Jun;4(3):276-80
references.pmid: 6233
references.citation: Addict Biol. 2006 Mar;11(1):55-63
references.pmid: 16759337
references.citation: Alcohol. 1986 Nov-Dec;3(6):383-8
references.pmid: 3814350
references.citation: Alcohol Clin Exp Res. 2008 Oct;32(10):1816-23
references.pmid: 18671810
references.citation: Mol Pharmacol. 1989 Aug;36(2):265-72
references.pmid: 2549383
references.citation: Psychopharmacology (Berl). 1999 Nov;147(1):81-9
references.pmid: 10591872
references.citation: Alcohol Clin Exp Res. 2001 Jan;25(1):25-33
references.pmid: 11198711
references.citation: J Neurosci. 2007 Mar 28;27(13):3593-602
references.pmid: 17392475
references.citation: Biol Psychiatry. 1987 Jan;22(1):35-42
references.pmid: 3790639
references.citation: FASEB J. 2008 Jul;22(7):2393-404
references.pmid: 18310464
references.citation: Psychopharmacology (Berl). 2001 Feb;154(1):43-9
references.pmid: 11292005
references.citation: J Pharmacol Exp Ther. 1998 Oct;287(1):284-92
references.pmid: 9765348
references.citation: Behav Brain Res. 2001 May;120(2):137-46
references.pmid: 11182162
references.citation: Eur J Pharmacol. 1984 Jul 13;102(2):229-35
references.pmid: 6541141
references.citation: Alcohol. 1998 May;15(4):281-9
references.pmid: 9590512
references.citation: Life Sci. 1980 Mar 3;26(9):679-88
references.pmid: 6767889
references.citation: Br J Pharmacol. 2006 Apr;147(8):864-72
references.pmid: 16491101
references.citation: Alcohol Clin Exp Res. 2001 Sep;25(9):1249-56
references.pmid: 11584142
references.citation: Alcohol Clin Exp Res. 1998 Sep;22(6):1185-9
references.pmid: 9756031
references.citation: Addict Biol. 2003 Jun;8(2):173-9
references.pmid: 12850776