Novel N-substituted 3α-[bis(4′-fluorophenyl)methoxy]tropane analogues:: Selective ligands for the dopamine transporter
Novel N-substituted 3α-[bis(4′-fluorophenyl)methoxy]tropane analogues:: Selective ligands for the dopamine transporter
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DOI：
10.1021/jm970525a
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发表时间：
1997-12-19
影响因子：
7.3
通讯作者：
Newman, AH
中科院分区：
文献类型：
--
作者：
Agoston, GE;Wu, JH;Newman, AH
已经制备了一系列N-取代的3 α-[双（4 '-氟苯基）甲氧基]托烷类似物，其用作多巴胺摄取抑制剂。该系列的N-甲基化类似物对多巴胺转运蛋白的亲和力显著高于母体化合物N-甲基-3 α-（二苯基甲氧基）托烷（benztropine，Cogentin）。然而，像母体化合物一样，它保留了对毒蕈碱受体的高亲和力。以去甲-3 α-[双（4 ′-氟苯基）甲氧基]托烷为原料，经酰化、氢化还原或直接烷基化，合成了一系列N-取代化合物。在大鼠尾壳核中，所有含有碱性托烷氮的化合物在多巴胺转运蛋白处置换[H-3]WIN 35，428（Ki范围= 8.5-634 nM）并阻断多巴胺摄取（IC 50范围= 10-371 nM），而具有非碱性氮的配体几乎无活性。没有一种化合物对去甲肾上腺素或5-羟色胺转运蛋白表现出高结合亲和力。重要的是，通过用其他N-烷基或芳烷基取代基取代N-甲基，实现了多巴胺转运蛋白与毒蕈碱m（i）受体的结合亲和力的分离（例如，正丁基、烯丙基、苄基、3-苯基丙基等）。此外，在多巴胺转运蛋白中，该系列中最有效和选择性的类似物N-（4“-苯基-正丁基）-3 α-[双（4 '-氟苯基）甲氧基]-托烷类似物未能在训练区分可卡因和盐水的大鼠中替代可卡因。潜在地，可能会发现开发可卡因滥用和其他影响多巴胺转运蛋白的疾病的药物的新线索。
A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha-(diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [H-3]WIN 35,428 at the dopamine transporter (K-i range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m(i) receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4 "-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]-tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.