Ound 5 potently inhibits alcohol self-administration in P-rats and binge-like Wistar rats
Ound 5 potently inhibits alcohol self-administration in P-rats and binge-like Wistar rats supports the idea that antagonism of k-opioid receptors may be of utility for full alcohol cessation functional activity. On the other hand, compared with naltrexone, the in vivo efficacy of compound 5 may not only be dependent on interaction with all the k-opioid receptor but also partial agonism in the m-opioid receptor. Presumably, the profile of opioid receptor binding coupled with the drug-like properties of compound five contributes to the optimal functional activity as an alcohol selfadministration inhibition agent in vivo. That is in agreement with current studies that show that an opioid with strong k-opioid receptor antagonism, albeit possessing some opioid agonism (i.e., nalmefene) (Bart et al., 2005), was far more successful at inhibition of alcohol self-administration than an opioid with broad opioid receptor antagonism (i.e., naltrexone) (Walker and Koob, 2008). Consequently, compound 5 and associated agents may well represent thrilling leads for the following generation of opioid compounds useful in the remedy of alcohol abuse.AcknowledgmentsThe authors thank Drs. Jarek Kalisiak and Marion Lanier for assistance with synthetic and analytical work; Dr. Sigeng Cheng for support with the animal perform; and Michael Ly and David Johnson at Microconstants, Inc., for the pharmacokinetic analytical work.Authorship ContributionsParticipated in study style: Cashman, Azar. Performed experiments: Cashman, Azar.JNK Formulation Cashman and AzarLi TK, Lumeng L, McBride WJ, and Murphy JM (1987) Rodent lines selected for elements affecting alcohol consumption. Alcohol Alcohol Suppl 1:916. MacDougall JM, Zhang XD, Polgar WE, Khroyan Television, Toll L, and Cashman JR (2004) Style, chemical synthesis, and biological evaluation of thiosaccharide analogues of morphine- and codeine-6-glucuronide. J Med Chem 47:5809815. Mason BJ, Salvato FR, Williams LD, Ritvo EC, and Cutler RB (1999) A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 56:71924. Mitchell JE, Morley JE, Levine AS, Hatsukami D, Gannon M, and Pfohl D (1987) High-dose naltrexone therapy and dietary counseling for obesity. Biol Psychiatry 22:352. Munro TA, Berry LM, Van’t Veer A, B uin C, Carroll FI, Zhao Z, Carlezon WA, Jr, and Cohen BM (2012) Long-acting k opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity. BMC Pharmacol 12:18. Osa Y, Ida Y, Fujii H, Nemoto T, Hasebe K, Momen S, Mochizuki H, and Nagase H (2007) Catalytic aerobic oxidation of nor-binaltorphimine (nor-BNI) analogs without the need of four,5-epoxy bridge affords a extra selective ligand for kappa opioid receptor than the representative kappa antagonist nor-BNI. Chem Pharm Bull (Tokyo) 55: 1489493. Oslin DW, Berrettini WH, and O’Brien CP (2006) Targeting ErbB3/HER3 drug therapies for alcohol dependence: the pharmacogenetics of naltrexone. Addict Biol 11:39703. Pastor R and Aragon CM (2006) The part of opioid receptor subtypes in the development of behavioral sensitization to ethanol. Neuropsychopharmacology 31: 1489499. Pettinati HM, O’Brien CP, Rabinowitz AR, Wortman SP, Oslin DW, Kampman KM, and Dackis CA (2006) The status of naltrexone within the remedy of alcohol dependence: precise effects on heavy drinking. J Clin Psychopharmacol 26:61025. Rassnick S, Pulvirenti L, and Koob GF (1993) SDZ-205,152, a novel dopamine receptor agonist, reduces oral ethanol self-administration in rats. Alcohol 10: 12732. Reid LD (1985) Endogenous opioid.