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SoRI 9409 and Ethanol Consumption PDF Print E-mail

Abstract for presentation at ISBRA 2006 World Congress on Alcohol Research and 2006 Research Society on Alcoholism

Abstract No: 847

SoRI 9409, a delta-opioid inverse agonist that produces a selective and long lasting reduction of ethanol consumption in rats

  • Dr. Carsten Nielsen, Ernest Gallo Clinic and Research Center, University of California San Francisco, United States
  • Mr. Jeff Simms, Ernest Gallo Clinic and Research Center, University of California San Francisco, United States
  • Dr. Sam Ananthan, Organic Chemistry Department, Southern Research Institute, Birmingham, United States
  • Dr. Selena Bartlett, Ernest Gallo Clinic and Research Center, University of California San Francisco, United States

The non-selective opioid antagonist, naltrexone, has been previously shown to reduce ethanol consumption in humans1, however other reports have indicated naltrexone to have limited therapeutic success.2

The free-access two-bottle choice method was used in Long-Evans rats to determine the effect on ethanol consumption of the naltrexone-derived compound, SoRI 94093, compared to naltrexone. Following stable drinking levels of ethanol (10% v/v), groups of rats (n=12) received SoRI 9409 (0, 5, 15, 30 mg/kg i.p.) or naltrexone (0, 1, 5, 10 mg/kg i.p.), with ethanol and water intake measured twice daily at 16 and 24 h following drug administration. To characterize SoRI 9409, the [35S]GTPgammaS binding and calcium mobilization assays were performed with HEK-293 cells stably transfected with either the cloned mouse mu-, delta- or kappa-opioid receptors.

Rats administered SoRI 9409 were found to have a significantly greater reduction in ethanol consumption than naltrexone (p<0.05), but without a reduction in water intake. Binding studies revealed SoRI 9409 to be a potent delta-inverse agonist. SoRI 9409 was also found to be a mu- and kappa-antagonist, as reported.3 Inhibition of selective opioid agonist (DPDPE, DAMGO, (-)U50,488H) stimulated binding showed that SoRI 9409’s opioid receptor antagonist action was ~25-fold more potent (delta), ~5-fold less potent (mu) and equipotent (kappa), compared with naltrexone.

As SoRI 9409 was found to produce a selective and long lasting reduction of ethanol consumption in rats with an apparent longer duration of action and a better side effect profile than that of naltrexone, it therefore appears to be a promising candidate for development as a novel therapeutic for the treatment of alcoholism.

1. O'Malley SS, Krishnan-Sarin S, Farren C, Sinha R, Kreek MJ. Psychopharmacol 1992; 160:19-29.
2. Swift RM. New Eng J Med 1999; 340:1482-90.
3. Xu H, Lu YF, Rice KC, Ananthan S, Rothman RB. Brain Res Bull 2001; 55:507-11.