COCAINE PHARMACOTHERAPIES: HETEROARYL ANALOGS OF 8-OXABICYCLOOCTANES

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。可卡因滥用潜在药物的开发主要集中在双环辛烷（3.2.1）的不同家族，其与单胺转运蛋白（多巴胺：DAT，5-羟色胺：SERT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，可卡因本身是双环[3.2.1]辛烷，但SERT也可能有助于可卡因的药理学作用。在一项旨在开发可卡因滥用药物的广泛调查中，我们先前证明，虽然8-氮杂双环（3.2.1）辛烷是有效的，但8-卡巴，8-氧杂和8-硫杂双环（3.2.1）辛烷对单胺转运蛋白具有显着的亲和力，通常与其8-氮杂对应物等效。为了开发SERT选择性摄取抑制剂，我们探索了在8-氧杂双环辛烷系列内的3-芳基环上引入杂芳基部分。基于先前的数据，表明2 β-甲氧羰基-3 β-芳基（椅）构型的化合物通常在DAT和SERT下表现出效力，而2 β-甲氧羰基-3 α-芳基（船）化合物通常在SERT下效力较低，我们制备了每类的代表性化合物。结果如下：具有杂芳基取代基的2 β-甲氧羰基-3 β-芳基（椅子）构型的化合物并不一致地显示出更高的SERT：DAT效力。几种化合物在SERT下相对有效，显示IC 50值小于50 nM，在DAT下有效性低2-10倍。有趣的是，辛烯类似物在两种转运蛋白上的有效性都大大低于其辛烷对应物。讨论：与母体8-氧杂托烷相比，船式和椅式化合物的SERT：DAT选择性都不高。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.