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首页> 外文期刊>Journal of Medicinal Chemistry >Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse.
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Slow-onset, long-duration 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers as potential medications to treat cocaine abuse.

机译：缓慢发作，持续时间较长的3-（3'，4'-二氯苯基）-1-茚满胺单胺再摄取阻滞剂可作为治疗可卡因滥用的潜在药物。

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A series of 3-(3',4'-dichlorophenyl)-1-indanamine monoamine reuptake blockers have been synthesized in an effort to develop a compound that could be used as a maintenance therapy to treat cocaine abuse. Since the effects of cocaine on dopamine (DA) and serotonin (5HT) transporters are important components of its pharmacological activity, the focus was on nonselective inhibitors of monoamine transport. To reduce or eliminate the abuse potential of a DA reuptake blocker, the compounds were designed to be slow-onset, long-duration prodrugs whose N-demethylated metabolites would have increased activity over the parent compound with the ideal being a parent compound that has little or no activity. To achieve this, pairs of compounds with different groups on the amine nitrogen and with and without an additional N-methyl group were synthesized. All of the synthesized compounds were screened for binding and reuptake at the cloned human DA, 5HT, and norepinephrine (NE) transporters. As previously found, trans isomers are nonselective blockers of DA, 5HT, and NE reuptake, cis isomers with small N-alkyl groups are selective blockers of 5HT reuptake, and tertiary amines of the trans compounds are less potent than the corresponding N-demethylated secondary amines as blockers of DA reuptake. Larger N-alkyl groups in both the trans and cis series were found to reduce activity for the 5HT and NE transporters with less effect at DA transporters. Selected trans compounds were also screened for locomotor activity in mice and generalization to a cocaine-like profile in rats. With intraperitoneal administration, all of the trans isomers showed a slow onset of at least 20 min and an extremely long duration of action in the locomotor assays. Several of the trans compounds also fully generalized to a cocaine-like pharmacological profile. An initial lead compound, the N,N-dimethyl analogue trans-1b, was resolved into chirally pure enantiomers. Surprisingly, both enantiomers were found to have significant affinity for the DA transporter and to cause locomotor activation. This is in contrast to the N-methyl compound in which only the (+)-enantiomer had significant activity. The absolute configuration of the more active enantiomer was determined by X-ray crystallography to be 3R,1S.
机译：合成了一系列3-（3'，4'-二氯苯基）-1-茚满胺单胺再摄取阻滞剂，以开发一种化合物，该化合物可用作维持治疗可卡因的滥用。由于可卡因对多巴胺（DA）和5-羟色胺（5HT）转运蛋白的作用是其药理活性的重要组成部分，因此重点是单胺转运的非选择性抑制剂。为了减少或消除DA再摄取阻滞剂的滥用可能性，将这些化合物设计为缓慢发作的长效前药，其N-去甲基代谢产物的活性将高于母体化合物，理想的是母体化合物很少或没有任何活动。为了实现这一点，合成了在胺氮上具有不同基团并且具有和没有额外的N-甲基的化合物对。筛选所有合成的化合物在克隆的人DA，5HT和去甲肾上腺素（NE）转运蛋白上的结合和重摄取。如先前发现，反式异构体是DA，5HT和NE重吸收的非选择性阻滞剂，带有小N-烷基的顺式异构体是5HT吸收的选择性阻滞剂，反式化合物的叔胺的效力不及相应的N-去甲基仲胺胺作为DA再摄取的阻滞剂。发现反式和顺式系列中较大的N-烷基基团降低了5HT和NE转运蛋白的活性，而对DA转运蛋白的作用较小。还筛选了选定的反式化合物在小鼠中的运动活性，并在大鼠中普遍化为可卡因样的特征。腹膜内给药时，所有的反式异构体在运动分析中显示至少20分钟的缓慢发作和极长的作用时间。几种反式化合物也完全泛化成可卡因样药理特性。将最初的先导化合物N，N-二甲基类似物trans-1b拆分为手性纯对映体。令人惊讶地，发现两种对映异构体对DA转运蛋白均具有显着的亲和力并引起运动活化。这与其中仅（+）-对映异构体具有显着活性的N-甲基化合物相反。通过X射线晶体学测定，更具活性的对映异构体的绝对构型为3R，1S。

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