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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Pharmacological Evaluation of 3-(3,4-Dichlorophenyl)-1-indanamine Derivatives as Nonselective Ligands for Biogenic Amine Transporters
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Synthesis and Pharmacological Evaluation of 3-(3,4-Dichlorophenyl)-1-indanamine Derivatives as Nonselective Ligands for Biogenic Amine Transporters

机译：3-（3,4-二氯苯基）-1-茚满胺衍生物作为生物胺转运蛋白的非选择性配体的合成及药理评价

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In our efforts toward developing a nonselective ligand that would block the effects of stimulants such as methamphetamine at dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-1-indanamine derivatives. Two of the examined higher affinity compounds had a phenolic hydroxyl group enabling preparation of a medium to long chain carboxylic acid ester that might eventually be useful for a long-acting depot formulation. The in vitro data indicated that (-)-(1R,3S)-trans-3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine ((-)-(1R,3S)-11) displays high-affinity binding and potent inhibition of uptake at all three biogenic amine transporters. In vivo microdialysis experiments demonstrated that intravenous administration of (-)-(1R,3S)-11 to rats elevated extracellular DA and 5-HT in the nucleus accumbens in a dose-dependent manner. Pretreating rats with 0.5 mg/kg (-)-(1R,3S)-11 elevated extracellular DA and 5-HT by approximately 150% and reduced methamphetamine-induced neurotransmitter release by about 50%. Ex vivo autoradiography, however, demonstrated that iv administration of (-)-(1R,3S)-11 produced a dose-dependent, persistent occupation of 5-HT transporter binding sites but not DA transporter sites.
机译：在我们努力开发一种非选择性配体的过程中，该配体会阻断多巴胺（DA）上的甲基苯丙胺，5-羟色胺（5-HT）和去甲肾上腺素（NE）转运蛋白等兴奋剂的作用，我们合成了一系列3-（3,4- （二氯苯基）-1-茚满胺衍生物。所研究的两个较高亲和力的化合物中的两个具有酚羟基，能够制备中链至长链羧酸酯，该酯最终可用于长效长效制剂。体外数据表明（-）-（1R，3S）-trans-3-（3,4-二氯苯基）-6-羟基-N-甲基-1-茚满胺（（-）-（1R，3S）- 11）在所有三种生物胺转运蛋白上均表现出高亲和力结合和对摄取的有效抑制。体内微透析实验表明，对大鼠进行静脉内（-）-（1R，3S）-11静脉内给药后，伏隔核中的细胞外DA和5-HT呈剂量依赖性。用0.5 mg / kg（-）-（1R，3S）-11预处理大鼠可使细胞外DA和5-HT升高约150％，并将甲基苯丙胺诱导的神经递质释放降低约50％。但是，离体放射自显影显示，静脉内给予（-）-（1R，3S）-11会产生剂量依赖性的5-HT转运蛋白结合位点的持久性占领，而不是DA转运蛋白位点。

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