Ound five 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 well be of utility for full alcohol cessation functional activity. Nonetheless, compared with naltrexone, the in vivo efficacy of compound 5 may not only be dependent on interaction using the k-opioid receptor but additionally partial agonism on the m-opioid receptor. Presumably, the profile of opioid receptor binding coupled together with the drug-like properties of compound 5 contributes towards the optimal functional activity as an alcohol selfadministration inhibition agent in vivo. This really is in agreement with current studies that show that an opioid with sturdy k-opioid receptor antagonism, albeit possessing some opioid agonism (i.e., nalmefene) (Bart et al., 2005), was far more powerful 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 related agents may well represent fascinating leads for the following generation of opioid compounds useful in the treatment of alcohol abuse.AcknowledgmentsThe authors thank Drs. Jarek Kalisiak and Marion Kinesin-7/CENP-E Formulation Lanier for help with synthetic and analytical work; Dr. Sigeng Cheng for assistance with the animal work; and Michael Ly and David Johnson at Microconstants, Inc., for the pharmacokinetic analytical perform.Authorship ContributionsParticipated in research design: Cashman, Azar. Performed experiments: Cashman, Azar.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 Tv, 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 5-HT5 Receptor manufacturer 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 four,5-epoxy bridge affords a far more 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 remedies for alcohol dependence: the pharmacogenetics of naltrexone. Addict Biol 11:39703. Pastor R and Aragon CM (2006) The role of opioid receptor subtypes within 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 in the therapy of alcohol dependence: certain 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.
