Vanoxerine National Institute on Drug Abuse.

Vanoxerine (GBR-12909) is a high-affinity dopamine reuptake inhibitor that was synthesized in the late 1970s and was initially tested in Europe as a potential antidepressant. In 1989, it was suggested that GBR-12909 might be useful in the treatment of cocaine addiction [346980]. The drug has completed phase I clinical trials conducted by the US National Institute on Drug Abuse for the potential treatment of cocaine abuse [346245,376621]. A multidose, safety and pharmacokinetics, open-label, fixed-order dose-escalating study has been completed. Four doses of vanoxerine in healthy normal volunteers were administered, to assess the safety and tolerability of the drug at 25, 50, 75 and 100 mg. Further development is likely to continue, pending review of the data [376621]. Dopamine transporter occupancy has also been measured. After 2 weeks of dosing at either 50, 75 or 100 mg oral vanoxerine in 8 human subjects, preliminary results of subsequent PET scans show that occupancy increased with dose, reaching 25 to 35% at 100 mg [346245]. At these doses, the drug did not cause the behavioral symptoms such as those of cocaine, suggesting that the drug does not have abuse potential. If no safety issues arise, the compound will be evaluated in trials with cocaine-dependent subjects, along with its derivative, compound 5 [346980]. It is thought that prolonged treatment with vanoxerine could reverse the addiction process, following studies in rats showing that dopamine transporter levels returned to normal when animals were switched to vanoxerine therapy immediately after cocaine administration [346980]. Vanoxerine has an affinity constant (Ki), at the human dopamine transporter, of 9 nM [347021]. Gist-Brocades originally initiated studies of vanoxerine, along with another piperazine, GBR-12935, for the treatment of cocaine dependence. The company was also investigating vanoxerine as a potential antipsychotic therapeutic agent; development for this indication has been discontinued [190331]. In 1995, the NIDA began to fund studies into the potential of vanoxerine to reduce cocaine self-administration by rhesus monkeys. Early data showed that vanoxerine could decrease cocaine-maintained responding (CMR) in rhesus monkeys, without affecting similar levels of food-maintained responding (FMR). Furthermore, a decanoate ester of a hydroxylated analog of vanoxerine, DBL-583, could decrease CMR by 80% while leaving FMR unaffected; this effect lasted almost 30 days with a single injection [227488,346980]. Similar studies have shown that, by inhibiting the dopamine transporter, for which vanoxerine has a 500-fold increased affinity in comparison to cocaine, vanoxerine could selectively reduce(1 mg/kg i.v.) or eliminate (3 mg/kg i.v.) cocaine self-administration in primates. The drug was well tolerated with no changes in blood pressure or oxygen saturation. Oral administration of the drug in clinical trials was planned following this study [346990].