多巴胺转运体绑定没有cocaine-like行为影响:苯托品类似物的合成和评估仅在啮齿动物,结合可卡因。

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Katz JL Agoston通用电气,Alling KL,克莱恩RH,福斯特MJ,伍尔弗顿西城,Kopajtic助教,纽曼啊

多巴胺转运体绑定没有cocaine-like行为影响:苯托品类似物的合成和评估仅在啮齿动物,结合可卡因。

精神药理学(Berl)。2001年4月,154 (4):362 - 74。

PubMed ID

11349389 (在PubMed

]

文摘

理由是:以前的SAR研究表明小diphenylether系统上的卤素取代的苯托品(BZT),比如para-Cl集团保留高亲和力的可卡因对多巴胺转运体结合位点。尽管如此高亲和力,化合物通常行为影响不同于可卡因。然而,化合物与meta-Cl替换效果更类似于可卡因。目的:一系列phenyl-ring类似物苯托品(BZT)和3 ',4 ' -取代,3”,4“- 4”,4”-安置Cl-groups合成及其药理学是为了评估更全面地评估这些位置的取代基对药理活性的贡献。方法:化合物合成和评估他们的药理作用是通过检查放射性配体结合和行为技巧。结果:所有的化合物[3 h]赢得35428人流离失所绑定亲和力从20到32.5纳米。亲和力在去甲肾上腺素([3 h] nisoxetine)和5 -羟色胺转运蛋白([3 h]西酞普兰),分别从259到5120和451到2980海里。每个化合物也抑制[3 h] pirenzepine绑定毒蕈碱的M1受体,亲和力从0.98到47.9纳米。可卡因和BZT类似物产生剂量增加小鼠的运动活动。然而,最大的影响BZT类似物均匀少于那些由可卡因,并获得2 - 3 h后注射相比相对快速发作(30分钟)的可卡因的影响。 In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.

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药物靶点

药物	目标	类	生物	药理作用	行动
Benzatropine	Sodium-dependent多巴胺转运体	蛋白质	人类	是的	抑制剂	细节