Bennett B A, Hollingsworth C K, Martin R S, Childers S R, Ehrenkaufer R E, Porrino L J, Davies H M
Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology and Radiology, Bowman Gray School of Medicine, Winston-Salem, NC 27157, USA.
Neuropharmacology. 1998;37(1):123-30. doi: 10.1016/s0028-3908(97)00194-9.
Cocaine and tropane analogs are known to interact with biogenic monoamine transporters by inhibiting amine uptake. Previous in vivo studies have demonstrated that some of these tropanes produce a longer lasting behavioral effect compared with cocaine. We have previously examined several tropane analogs and found a difference in their relative affinities for dopamine (DA) and serotonin (5-HT) transporters. The purpose of this study was to determine the recovery time of transporter function in vitro and in vivo comparing cocaine with the tropane analogs WF-11 (PTT, selective for DA transporters), WF-31 (selective for 5-HT transporters) and WF-23 (highly potent at both DA and 5-HT transporters). In vitro, using primary rat brain cultures of either midbrain or raphe regions, the recovery of the ability to transport either [3H]dopamine or [3H]serotonin, respectively was evaluated at 0, 3, 24, 48, 120 and 240 h after a 1 h exposure to cocaine and tropane analogs. The tropanes exhibited clearance half-lives ranging from 12 to 69 h, while cocaine, on the other hand, exhibited a clearance half-life of approximately 6 h. In studies utilizing [125I]RTI-55 binding, intraperitoneal injections of cocaine and WF-23 into the rat resulted in striatal clearance half-lives ex vivo that were almost identical to those obtained in vitro. These data suggest that the tropanes bind to and reduce transporter function for prolonged periods of time (up to 10-fold longer than cocaine) and those compounds with the highest affinity may produce a pseudo-irreversible inhibition of transporter function.
可卡因和托烷类似物已知可通过抑制胺摄取与生物源性单胺转运体相互作用。先前的体内研究表明，与可卡因相比，其中一些托烷产生的行为效应持续时间更长。我们之前研究了几种托烷类似物，发现它们对多巴胺（DA）和5-羟色胺（5-HT）转运体的相对亲和力存在差异。本研究的目的是在体外和体内比较可卡因与托烷类似物WF-11（PTT，对DA转运体具有选择性）、WF-31（对5-HT转运体具有选择性）和WF-23（对DA和5-HT转运体均具有高效能）的转运体功能恢复时间。在体外，使用中脑或中缝区域的原代大鼠脑培养物，在暴露于可卡因和托烷类似物1小时后的0、3、24、48、120和240小时分别评估转运[3H]多巴胺或[3H]5-羟色胺能力的恢复情况。托烷的清除半衰期为12至69小时，而可卡因的清除半衰期约为6小时。在利用[125I]RTI-55结合的研究中，向大鼠腹腔注射可卡因和WF-23导致纹状体离体清除半衰期与体外获得的几乎相同。这些数据表明，托烷可长时间结合并降低转运体功能（比可卡因长10倍），且那些具有最高亲和力的化合物可能对转运体功能产生假不可逆抑制。
