Zhang Shijun, Fernandez Fernando, Hazeldine Stuart, Deschamps Jeffrey, Zhen Juan, Reith Maarten E A, Dutta Aloke K
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, USA.
J Med Chem. 2006 Jul 13;49(14):4239-47. doi: 10.1021/jm0601699.
In our previous report, we described a novel series of asymmetric pyran derivatives (2S,4R,5R)-2-benzhydryl-5-benzylamino-tetrahydropyran-4-ol and their enantiomers as blockers of monoamine transporters in the brain. In this report, we describe the further exploration of this series of molecules by incorporating functional groups in the molecular template, which should promote the formation of H bonds with the transporters. In addition, a new synthetic scheme for the asymmetric synthesis of disubstituted cis-(6-benzhydryl-tetrahydro-pyran-3-yl)-benzylamine analogues and their biological characterization is reported. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. The compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [(3)H]WIN 35, 428. The results indicated that the presence of functional groups, such as -OH, -NH(2), and the bioisosteric 5-substituted indole moiety in both di and trisubstituted compounds, significantly increased their potencies for the SERT and NET, especially for the NET. Among the trisubstituted compounds, (-)-4b exhibited the highest potency for the NET and the SERT (K(i) of 2.13 and 15.3 nM, respectively) and was a serotonin norepinephrine reuptake inhibitor (SNRI). Compound (-)-4a exhibited the highest selectivity for the NET. Among the disubstituted compounds, a number of compounds, such as (-)-9a, (+)-9b, (-)-9b, and (+)-9d, exhibited significant low-nanomolar potencies for the SERT and the NET. Interestingly, compound (-)-9d exhibited appreciable potencies at all three transporters. On the basis of our present and past findings, we propose a qualitative model for the interaction of these compounds with monoamine transporters, which will be refined further in the future.
在我们之前的报告中，我们描述了一系列新型的不对称吡喃衍生物（2S,4R,5R）-2-二苯甲基-5-苄基氨基-四氢吡喃-4-醇及其对映体，它们是大脑中单胺转运体的阻滞剂。在本报告中，我们描述了通过在分子模板中引入官能团对这一系列分子的进一步探索，这应该会促进与转运体形成氢键。此外，还报道了一种用于不对称合成二取代顺式-（6-二苯甲基-四氢-吡喃-3-基）-苄胺类似物的新合成方案及其生物学特性。通过分别测量它们抑制[(3)H]DA、[(3)H]5-HT和[(3)H]NE摄取的效力，对所有合成的衍生物进行了大脑中多巴胺转运体（DAT）、5-羟色胺转运体（SERT）和去甲肾上腺素转运体（NET）亲和力的测试。还通过它们抑制[(3)H]WIN 35,428结合的能力测试了这些化合物在DAT上的结合效力。结果表明，在二取代和三取代化合物中，诸如-OH、-NH(2)以及生物电子等排体5-取代吲哚部分等官能团的存在显著提高了它们对SERT和NET的效力，尤其是对NET。在三取代化合物中，(-)-4b对NET和SERT表现出最高的效力（K(i)分别为2.13和15.3 nM），并且是一种5-羟色胺去甲肾上腺素再摄取抑制剂（SNRI）。化合物(-)-4a对NET表现出最高的选择性。在二取代化合物中，许多化合物，如(-)-9a、(+)-9b、(-)-9b和(+)-9d，对SERT和NET表现出显著的低纳摩尔效力。有趣的是，化合物(-)-9d在所有三种转运体上都表现出可观的效力。基于我们目前和过去的研究结果,我们提出了这些化合物与单胺转运体相互作用的定性模型,该模型将在未来进一步完善。
