IRREVERSIBLE ANTAGONISTS OF COCAINE AND OTHER STIMULANTS

这里提出的工作的目的是合成化合物。 它将拮抗补益和诱发精神疾病的特性 可卡因刺激物的不可逆结合与刺激物识别 多巴胺转运体上的位置。此方法基于以前的 对甲氧苯丙胺的研究结果，这是一种酰化苯环利定衍生物，在 体外不可逆转地抑制末端和运输 多巴胺神经末梢。在体内，Metaphit完全阻断 多动症通常见于服用可卡因和 其他兴奋剂。 可卡因和其他兴奋剂的潜在不可逆转拮抗剂将 通过在已知化合物中添加活性亲电基团来合成 作为兴奋剂与多巴胺结合的有效抑制剂 运输者，以及运输过程本身。这些化合物 被选中进行修饰的是芳基的“GBR”系列化合物mazindol 1，4-二(En)基哌嗪、哌甲酸甲酯和多巴胺本身。这个 要引入到其结构中的反应基团是 异硫氰酸酯、溴乙酰胺、马来酰亚胺和氟磺酰基。 新合成的化合物将与Fourphit(A)一起进行筛选 由外部合作者提供给我们的MetapHit的异构体) 不可逆地与多巴胺转运体相互作用的能力。这将是 通过测量(1)它们对兴奋剂的抑制活性来确定 [~3H]哌醋甲酯放射受体分析中的识别位点和(2) 它们能够不可逆转地阻止[~3H]多巴胺摄取进入突触体。 多巴胺转运体对去甲肾上腺素的选择性 5-羟色胺转运体将被确定。被发现的化合物不可逆转地 在一定程度上抑制兴奋剂结合和多巴胺摄取 然后，将在体内测试它们的行为影响。 化合物的活性将在三个不同的行为中进行检查 旨在评估它们的潜力以对抗 增强和急、慢性精神错乱诱发特性 人体内的兴奋剂。表现出行为活性的化合物将 然后在体外测试它们阻断[~3H]哌醋甲酯的能力 结合和[~3H]多巴胺摄取。这将需要检查 [~3H]哌醋甲酯结合与体外脑组织多巴胺摄取 取自体内用这些化合物处理的大鼠。的代谢物 多巴胺也将在使用兴奋剂治疗后进行检测。 拮抗剂，以关联刺激性拮抗剂的特性 合成的化合物及其对多巴胺周转的影响。这 研究将使我们能够开发潜在的兴奋剂拮抗剂 滥用职权。它还为最终的孤立和 多巴胺转运复合体的纯化。

The purpose of the work proposed here is to synthesize compounds which will antagonize the reinforcing and psychosis-inducing properties of cocaine stimulants by binding irreversibly to the stimulant recognition site on the dopamine transporter. This approach is based on previous findings with Metaphit, an acylating phencylidine derivative, which in vitro irreversibly inhibits both the terminals as well as the transport of dopamine nerve terminal.In vivo, Metaphit completely blocks the hyperactivity normally seen following the administration of cocaine and other stimulants. Potential irreversible antagonists of cocaine and other stimulants will be synthesized by adding reactive electrophilic groups to compounds known to be effective inhibitors both of stimulant binding to the dopamine transporter, as well as of the transport process itself. The compounds selected for modification are mazindol, the "GBR' series of aryl 1,4-dialk(en)ylpiperazines, methylphenidate, and dopamine itself. The reactive groups to be introduced into their structures are the isothiocyanate, bromoacetamide, maleimide, and fluorosulfonyl moieties. The newly synthesized compounds will be screened, along with Fourphit (a isomer of Metaphit provided to us by an outside collaborator) for their ability to interact irreversibly with the dopamine transporter. This will be determined by measuring (1) their inhibitory activity at the stimulant recognition site in the [3H]methylphenidate radioreceptor assay and (2) their ability to irreversibly block [3H]dopamine uptake into synaptosomes. Selectivity for the dopamine transporter over the norepinephrine and serotonin transporter will be determined. Compounds found to irreversibly inhibit stimulant binding and dopamine uptake with some degree of selectivity will then be tested in vivo for their behavioral effects. Activity of the compounds will be examined in three separate behavioral paradigms designed to evaluate their potential to antagonize the reinforcing and acute and chronic psychosis-inducing properties of stimulant agents in humans. Compounds which show behavioral activity will then be tested Ex vivo for their ability to block [3H]methylphenidate binding and [3H]dopamine uptake. This will entail examining [3H]methylphenidate binding and dopamine uptake in vitro from brain tissue taken from rats treated with these compounds in vivo. Metabolites of dopamine will also be measured following treatment with the stimulant antagonists in order to correlate the stimulant antagonist properties of the synthesized compounds with their effect on dopamine turnover. This research will enable us to develop potential antagonists of stimulant drugs of abuse. It also lays the groundwork for the eventual isolation and purification of the dopamine transport complex.