COCAINE PHARMACOTHERAPIES: HETEROARYL ANALOGS OF 8-OXABICYCLOOCTANES

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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.