Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate.
Synthesis and pharmacology of site-specific cocaine abuse treatment agents: restricted rotation analogues of methylphenidate.
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位点特异性可卡因滥用治疗剂的合成和药理学：哌醋甲酯的限制旋转类似物。
DOI：
10.1021/jm061354p
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发表时间：
2007
影响因子：
7.3
通讯作者：
Schweri,MargaretM
中科院分区：
文献类型：
--
作者：
Kim,Deog-Il;Deutsch,HowardM;Ye,Xiaocong;Schweri,MargaretM
合成了一系列苏型-1-氮杂-3或4-取代-5-苯基[4.4.0]癸烷（喹嗪啶），它们被设想为哌甲酯（MP）的限制性旋转类似物（RRA），并测试了对[3 H] WIN 35，428，[3 H]西酞普兰和[3 H]尼索西汀分别与多巴胺，5-羟色胺和去甲肾上腺素转运蛋白结合的抑制效力。使用了两种不同的合成方案;维蒂希反应或酰化（随后是分子内缩合）是每种方案的关键特征。未取代的RRA，苏型（反式）-1-氮杂-5-苯基[4.4.0]癸烷（12 a），对[3 H] WIN 35，428结合的抑制力与未限制的苏型MP相当。这些RRA中的额外环（其降低构象自由度）以及在该额外环上的4-位上的取代基的取向和极性对生物活性至关重要。通常，RRA在与三种转运蛋白的结合亲和力方面优于相应的不受约束的MP衍生物。结果表明，甲基酯的羰基与哌啶基N-H键合的MP构象可能是该分子的生物活性形式。
A series ofthreo-1-aza-3 or 4-substituted-5-phenyl[4.4.0]decanes (quinolizidines), which were envisioned as restricted rotational analogues (RRAs) of methylphenidate (MP), was synthesized and tested for inhibitory potency against [3H]WIN35,428, [3H]citalopram, and [3H]nisoxetine binding to the dopamine, serotonin, and norepinephrine transporters, respectively. Two different synthetic schemes were used; a Wittig reaction or acylation (followed by an intramolecular condensation) was a key feature of each scheme. The unsubstituted RRA,threo(trans)-1-aza-5-phenyl[4.4.0]decane (12a), was equipotent to unconstrainedthreo-MP against [3H]WIN35,428 binding. The extra ring in these RRAs (which reduces the conformational freedom) and the orientation and polarity of substituents at the 4-position on this extra ring are of critical importance to the biological activity. Generally, the RRAs paralleled the corresponding unconstrained MP derivatives in binding affinity to the three transporters. The results suggest that the conformation of MP in which the carbonyl group of the methyl ester is H-bonded to the piperidinyl N−H may be the bioactive form of the molecule.