Anti-addictive properties of COR659 - Additional pharmacological evidence and comparison with a series of novel analogues

A recent study found that COR659 (methyl 2-[(4-chlorophenyl)carboxamido]-4-ethyl-5-methylthiophene-3-carboxylate) reduced operant alcohol and chocolate self-administration in rats; COR659 also suppressedcue-induced reinstatement of chocolate seeking in rats. COR659 apparentlyexerts its effectsviaa compositemechanism, including positive allostericmodulationof theGABABreceptor andanaction at thecannabinoidCB1receptor.ThepresentstudyinvestigatedwhetherthereducingeffectofCOR659onalcoholandchocolateself-administration was maintained after repeated treatment and if COR659 affected cue-induced rein-statement of alcohol seeking; additionally, it evaluated the ability of 9 structural analogues of COR659edesigned modifying the substituents on the phenylcarboxamido moiety and replacing the thiophene withthe pyridine ringeto affect alcohol and chocolate self-administration. Alcohol self-administration experi-ments employed Sardinian alcohol-preferring (sP) rats trained to lever-respond for alcohol (15% v/v).Chocolate self-administration experiments employed Wistar rats trained to lever-respond for a chocolatesolution (5% w/v Nesquik®). In the reinstatement experiment, previously extinguished lever-responding foralcohol in sP rats was reinstated by the non-contingent presentation of an alcohol-associated complex ofcues. All drugs were tested at the doses of 0, 2.5, 5, and 10 mg/kg (i.p.). 10-Day treatment with COR659produced a dose-related reduction of both alcohol and chocolate self-administration, with limited loss ofefficacy on continuing treatment. Acute COR659 suppressed reinstatement of alcohol seeking. Among the 9tested analogues, only COR657 (methyl 2-(benzoylamino)-4-ethyl-5-methylthiophene-3-carboxylate)decreased alcohol self-administration similarly to COR659; all other compounds produced modest, or evenno, effect on alcohol self-administration. COR659 excluded, no compound altered chocolate self-administration. These results confirm and extend the ability of COR659 to reduce several behaviors moti-vatedbyalcoholandpalatablefoodinrats.ComparisonofCOR659toitsanaloguesprovideddisparateresultsthatdo not currentlyallowanyconclusive structure-activity relationship to behypothesized,astheirdiversepharmacological profile apparently does not depend on physicochemical properties