COCAINE PHARMACOTHERAPIES: HETEROARYL ANALOGS OF 8-OXABICYCLOOCTANES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。针对可卡因滥用的潜在药物的开发主要集中在自行车(3.2.1)辛烷的多样化家族上，这些辛烷能与单胺转运体(多巴胺：DAT、5-羟色胺：丝氨酸乙酯和去甲肾上腺素：NET)有效结合。DAT与可卡因的药理学密切相关，可卡因本身是一种双环[3.2.1]辛烷，但SERT也可能与可卡因的药理作用有关。在一项旨在开发治疗可卡因滥用药物的广泛调查中，我们先前证明了8-氮杂双环(3.2.1)辛烷是有效的，而8-Carba、8-oxa和8-硫杂环(3.2.1)辛烷对单胺转运体具有显著的亲和力，通常等同于它们的8-aza对应物。为了开发SERT选择性摄取抑制剂，我们探索了在8-氧杂二环辛烷系列的3-芳环上引入杂芳基部分。基于先前的数据表明，2β-甲氧基-3β-芳基(椅子)结构的化合物通常在DAT和SERT上都表现出效力，而2β-甲氧基-3α-芳基(BOAT)化合物在SERT上的效力通常较弱，我们从每一类化合物中制备了具有代表性的化合物。结果：2具有杂芳基的β-甲氧基-3-β-芳基(椅子)构型化合物并不总是表现出更高的SERT：DAT势。几种化合物在SERT中的效力相对较强，其IC50值小于50 nm，而在DAT中的效力则低2-10倍。有趣的是，辛烯类似物在两种转运体上的效力都比它们的辛烷类似物弱得多。讨论：与母体8-氧托烷相比，船和椅子都有适度的SERT：DAT选择性。开发对SERT表现出比DAT更高效力的可卡因类似物是可行的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The development of potential medications for cocaine abuse has focused largely on the diverse family of bicycle(3.2.1)octanes, that bind potently to monoamine transporters (dopamine: DAT, serotonin: SERT and norepinephrine: NET). DAT is strongly implicated in the pharmacology of cocaine, itself a bicyclo[3.2.1]octane, but the SERT may also contribute to the pharmacological effects of cocaine. In an extensive investigation aimed at developing medications for cocaine abuse, we previously demonstrated that while 8-azabicyclo(3.2.1)octanes are potent, 8-carba, 8-oxa, and 8-thia bicycle(3.2.1)octanes have significant affinity for monoamine transporters, frequently equipotent to their 8-aza counterparts. To develop SERT selective uptake inhibitors, we explored the introduction of heteroaryl moieties on the 3-aryl ring within the 8-oxabicyclooctane series. Based on previous data indicating that 2beta-carbomethoxy-3beta-aryl (chair) configured compounds generally manifest potency at both DAT and SERT whereas the 2beta-carbomethoxy-3alpha-aryl (boat) compounds are generally less potent at SERT, we prepared representative compounds from each class. Results: 2beta-carbomethoxy-3beta-aryl (chair) configured compounds with heteroaryl substituents did not consistently display higher SERT:DAT potencies. Several compounds were relatively potent at the SERT, displaying IC50 values less than 50 nM, and were 2-10 fold less potent at the DAT. Intriguingly, octene analogs were considerably less potent at both transporters than the their octane counterparts. Discussion: In contrast to the parent 8-oxatropanes, both the boat and chair compounds modest SERT:DAT selectivity. It is feasible to develop cocaine analogs that manifest higher potency for the SERT than DAT.