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].