DOPAMINE TRANSPORTER AGENTS AGAINST COCAINE DEPENDENCE

点击翻译按钮获取中文摘要

Cocaine is a strong reinforcer which led to its wide-spread use as a major drug of abuse in U.S.A in the last two decades. The development of a medication to treat this addiction is an urgent requirement. The central mechanism of the action of cocaine is attributed to its binding to the dopamine (DA) transporter system in the brain. Many structurally diverse compounds that bind selectively to the DAT, have been developed with an aim to block cocaine dependence in the central nervous system (CNS), but they met with only limited success. Recently, a high affinity DAT- specific compound GBR 12909 was found to have longer duration of action, was self-administered less potently than cocaine, and could antagonize some of the cocaine action. In our structure- activity relationship (SAR) study, we have shown the development of novel piperidine analogs of GBR 12909-related potent DAT- specific compounds. Our follow-up SAR study led to the development of a second generation of compounds in this class with far more selectivity for the DAT than conventional GBR molecules. In one of our recent studies, replacement of the benzhydrylic O-atom by an N-atom is these DAT-specific compounds, led to the development of potent and more polar, new-generation N-analog molecules. Furthermore, some of our analogs showed remarkable selectivity for binding to the cocaine binding site compared to the dopamine reuptake site in the cloned human transporters binding assay. The values of their uptake to binding ratio were far greater than values of any other existing compounds. In our initial in-vivo motor action studies in mice, two of these analogs were less stimulatnt than cocaine and GBR 12909 at similar doses. In combination studies with cocaine, these compounds attenuated the locomotor stimulatory effect of cocaine efficiently. We now propose to follow up on the SAR studies of our lead compounds to develop potent and selective compounds for the DAT with high dopamine uptake to binding ratio. Selected compounds will be tested for their effects on locomotor action and drug discrimination studies to observe their ability to block cocaine action. Our goal is to develop an effective medication against cocaine addiction.