Cocaine maintenance therapy? Several different R (proton or alkyl group) substitutions of the general structure, shown above, display binding properties to the dopamine transporter similar to that of cocaine, but with significantly slower mechanisms of action.

Researchers are closer to devising a treatment for cocaine addiction that would allow users to break the habit without experiencing extreme cravings during withdrawal.

Maintenance therapies, as they are called, already help heroin addicts end their dependence. The compounds methadone and levo--acetylmethadol soothe the physical symptoms of withdrawal, making it easier for users to wean themselves from heroin. However, there are no analogous substances for cocaine abusers. The only option is to quit abruptly, which means weathering intense pangs, says chemist Mark Froimowitz of Pharm-Eco Laboratories in Devens, MA.

Froimowitz says that the ideal maintenance therapy for cocaine should reduce cravings without being addictive or “abusable”. What makes cocaine abusable is that it induces a very rapid high that fades quickly, requiring an other dose to maintain the pleasure. Cocaine elicits this euphoric rush by binding to transporter molecules that sweep dopamine from brain synapses. When the transporters are blocked in this manner, dopamine remains in the synapse and the neurons continue to fire. Therefore, target molecules for maintenance therapy should bind to the dopamine transporter, as cocaine does, but should act more slowly and for a longer amount of time.

With this in mind, Froimowitz and colleagues synthesized 27 compounds, generally known as dichlorophenyl-indanamines, and tested their binding activity to the human dopamine transporter. Like cocaine, many of the indanamines fastened tightly to the transporter (J. Med. Chem. 2000, 43, 4981–4992), satisfying the first requirement for a maintenance therapy.

To determine whether the molecules had the necessary slow-onset, long-duration profile, the researchers studied rats that had taken cocaine or one of eight indanamines. Within 10 min of a cocaine dose, the rats were highly stimulated, but their movements declined to nearly normal within 2 h. With several indanamines, however, increased activity was not ap parent for 20 min and lasted at least 8 h.

These results look promising, and the team has already begun investigating a different family of molecules that provides the same benefits while causing less agitation. Froimowitz cautions, though, that it will be several years before any such treatment is available in clinics.