Cocaine is one of the most powerfully addictive drugs known, exerting its effect by acting directly on the reward or pleasure centers of the brain. Cocaine abuse has imposed a burden on public health and public safety worldwide, by playing an important role in the rapid spread of acquired immune deficiency syndrome and drug-resistant tuberculosis. The literature suggests that binding to the dopamine transporter and subsequent inhibition of dopamine reuptake may be responsible for its reinforcing property and locomotor activity. We designed and synthesized a series of analogs related to GBR 12935 and GBR 12909 in which the piperazine moiety was replaced by bridged piperazines for structural rigidity. These were evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of [3H]-labeled dopamine (DA). The N-indolylmethyl analog showed the highest affinity of the series, with a 6-fold increase over its corresponding N-phenypropyl derivative. Interestingly, it also exhibited a high ratio (29-fold) for the inhibition of dopamine reuptake versus binding to the DAT. Substitution of the homopiperazine moiety with a rigid 3,9-diazabicyclo[4.2.1] decreased affinity at DAT, and selectivity at the DAT relative to serotonin transporter compared to its corresponding homopiperazine.Other lines of evidence suggest that the strategy of developing selective and high affinity DA uptake inhibitors for the treatment of cocaine abuse may be misplaced. It was noted in the literature that dopamine transporter knockout mice self-administered, indicating that in the absence of the DA transporter, cocaine can still establish rewarding effects. To investigate this new paradigm, we designed a series of methoxy-containing derivatives of indatraline to obtain a template for the development of a long-acting inhibitor of monoamine transporters. Introduction of a methoxy group to indatraline affected affinity and selectivity greatly. Some of the analogues were more selective than indatraline and a 6-methoxy derivative displayed the highest affinity for both serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for long-acting ligands with potential as medication for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.
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