Non-amines, drugs without an amine nitrogen, potently block serotonin transport: Novel antidepressant candidates?
Non-amines, drugs without an amine nitrogen, potently block serotonin transport: Novel antidepressant candidates?
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DOI：
10.1002/syn.1108
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发表时间：
2001-12-01
期刊：
影响因子：
2.3
通讯作者：
Madras, BK
中科院分区：
文献类型：
--
作者：
Goulet, M;Miller, GM;Madras, BK
血清素转运蛋白（SERT）是治疗性抗抑郁药在大脑中的主要作用部位。这些血清素转运抑制剂无一例外地在其结构中含有胺氮。我们之前证明，结构中不含胺氮的新型化合物（非胺）可以阻断转染人多巴胺转运蛋白的细胞中的多巴胺转运。本研究调查了在没有胺氮的情况下，某些非胺是否选择性地与 SERT 结合并阻止血清素的转运。在 10 μM 浓度下，选择的非胺对 9 种血清素、5 种多巴胺、7 种肾上腺素能受体、5 种鼠碱胆碱能受体、3 种阿片剂和组胺受体没有或几乎没有亲和力。在 HEK-293 中稳定或瞬时表达的克隆人 SERT 中测量非胺对 SERT 上 [H-3] 西酞普兰结合位点的亲和力及其阻断 [H-3] 血清素转运的效力。无论是基于 oxa 基还是 carba 基，非胺都会与 [H-3] 西酞普兰标记位点结合，并在低纳摩尔范围内阻断 PHI 血清素转运，其值等于或高于一些常规抗抑郁药。非胺（0-1809）对血清素的选择性比多巴胺转运蛋白高 99 倍。由于非胺芳香环上的取代基赋予 SERT 高亲和力，我们研究了芳香族-芳香族相互作用可能对非胺/转运蛋白缔合有显着贡献的假设。产生了 SERT 突变体，其中高度保守的芳香族氨基酸苯丙氨酸 548 被丙氨酸 (F548A) 取代。尽管突变 SERT 中几种非胺的亲和力没有变化，但丙咪嗪的亲和力却降低了，这揭示了 SERT 上胺和非胺结合域可能存在的差异。非胺类药物和传统抗抑郁药物对 SERT 的相似亲和力支持这样的观点，即胺氮对于以高亲和力阻断血清素转运的药物来说并不是必需的。非胺为开发新一代抗抑郁药开辟了道路。 (C) 2001 Wiley-Liss, Inc.
The serotonin transporter (SERT) is a principal site of action of therapeutic antidepressants in the brain. Without exception, these inhibitors of serotonin transport contain an amine nitrogen in their structure. We previously demonstrated that novel compounds without an amine nitrogen in their structure (non-amines), blocked dopamine transport in cells transfected with the human dopamine transporter. The present study investigated whether, in the absence of an amine nitrogen, certain non-amines bind selectively to the SERT and block the transport of serotonin. At 10 muM concentration, select non-amines displayed no, or little, affinity for 9 serotonin, 5 dopamine, 7 adrenergic, 5 musearinic cholinergic, 3 opiate and histamine receptors. The affinities of non-amines for [H-3]citalopram binding sites on the SERT and their potencies for blocking [H-3]serotonin transport were measured in cloned human SERT stably or transiently expressed in HEK-293. Whether oxa- or carba-based, non-amines bound to [H-3]citalopram-labeled sites and blocked PHIserotonin transport in the low nanomolar range, at values equal to or higher than those of some conventional antidepressants. A non-amine, 0-1809, was 99-fold more selective for the serotonin over the dopamine transporter. As substituents on the aromatic ring of non-amines confer high affinity for the SERT, we investigated the hypothesis that aromatic-aromatic interactions may contribute significantly to non-amine/transporter association. A SERT mutant was produced in which a highly conserved aromatic amino acid, phenylalanine, 548, was replaced by an alanine (F548A). Although the affinities of several non-amines were unchanged in the mutant SERT, the affinity of imipramine was decreased, revealing possible differences in amine and non-amine binding domains on the SERT. The similar affinities of non-amines and conventional antidepressant drugs for the SERT support the view that an amine nitrogen is not essential for drugs to block serotonin transport with high affinity. Non-amines open avenues for developing a new generation of antidepressants. (C) 2001 Wiley-Liss, Inc.