Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor.
Synthesis and receptor binding of N-substituted tropane derivatives. High-affinity ligands for the cocaine receptor.
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N-取代托烷衍生物的合成和受体结合。
DOI：
10.1021/jm00109a029
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发表时间：
1991
影响因子：
7.3
通讯作者：
Neumeyer,JL
中科院分区：
文献类型：
--
作者：
Milius,RA;Saha,JK;Madras,BK;Neumeyer,JL
报道了一系列 N-取代的 3-(4-氟苯基)托烷衍生物的合成和药理学表征。这些化合物表现出与可卡因相似的结合特性，并且其中几种在可卡因识别位点具有更高的亲和力。将4-氟苯基溴化镁与脱水芽子碱甲酯共轭加成，经过快速色谱法后得到2/S-(甲甲氧基)-3/3-(4-氟苯基)托烷(4a，指定为CFT，也称为WIN 35,428)。通过 Zn/HOAc 还原相应的 2, 2, 2-三氯乙基氨基甲酸酯，进行 4a 的 N 脱甲基化，得到 2<3-甲氧基-3/3-(4-氟苯基)去甲托烷 (5)，用烯丙基溴将其烷基化为 Etfford N-Etllyl 类似物 6。通过催化还原制备 N-丙基类似物 7 (Pd/C) 为 6。最有效的类似物 4a 以 81.3 Ci/mmol 的比活度进行氚化。[3H] 4a 快速可逆地与尾壳核膜 Etnd 结合；观察到可卡因和 Eilogues 典型的双组分结合曲线。 2 小时内达到平衡，并稳定至少 4 小时。 [3H] 4a 观察到的高亲和力和低亲和力 K¿ 值（分别为 4.7 和 60 nM）比 [3H] 可卡因低 4 倍以上，并且两种药物的结合位点密度（S^= 50 pmol/g，高和 290 pmol/g，低）相当。 [3H]4a的非特异性结合占总结合的5-10%。可卡因的滥用是全国关注的公共卫生问题。尽管在这一领域做出了巨大的努力，但仍然缺乏关于介导可卡因行为效应和滥用倾向的神经化学机制的足够信息。 1 已在啮齿类动物、2" 5 非人类灵长类动物、6 和人类的纹状体组织中鉴定出 [3H] 可卡因的选择性药理学相关结合位点。7 这些位点与单胺摄取系统相关，并显示出药理学受体的特性特征。具体来说，这些位点可饱和且可逆地结合 [3H] 可卡因，8, 9 它们显示出对 (-)-可卡因相对于其的立体选择性。对映异构体 (+)-可卡因或其 C-2 差向异构体、伪可卡因 6，并且它们在各种可卡因类似物的结合亲和力与其抑制多巴胺摄取 6 和产生可卡因样行为效应（如行为刺激）、10 静脉自我给药、11 和刻板性 2 的相对效力之间表现出高度的相关性。它们与多巴胺再摄取系统的关系受到[3H]可卡因作为放射性配体探针的限制。
The synthesis and pharmacological characterization of a series of N-substituted 3-(4-fluorophenyl) tropane derivatives is reported. The compounds displayed binding characteristics that paralleledthose of cocaine, and several had substantially higher affinity at cocaine recognition sites. Conjugate addition of 4-fluorophenylmagnesium bromide to anhydroecgonine methyl ester gave 2/S-(carbomethoxy)-3/3-(4-fluorophenyl) tropane (4a, designated CFT, also known as WIN 35,428) after flash chromatography. N demethylation of 4a was effected by Zn/HOAc reduction of the corresponding 2, 2, 2-trichloroethyl carbamate to give 2< 3-carbomethoxy-3/3-(4-fluorophenyl) nortropane (5), which wes alkylated with allyl bromide to Etfford the JV-Etllyl analogue, 6. The N-propyl analogue, 7, was prepared by catalytic reduction (Pd/C) of 6. The most potent analogue, 4a, was tritiated at a specific activity of 81.3 Ci/mmol.[3H] 4a bound rapidly Etnd reversibly to caudate putamen membranes; the two-component binding curve typical of cocaine anEilogues weis observed. Equilibrium weis achieved within 2 h and was stable for at least 4 h. High-and low-affinity K¿ values observed for [3H] 4a (4.7 and 60 nM, respectively) were more than 4 times lower than those for [3H] cocaine, and the density of binding sites (S^= 50 pmol/g, high, and 290 pmol/g, low) for the two drugs were comparable. Nonspecific binding of [3H] 4a was 5-10% oftotal binding.The abuse of cocaine is a public health problem of great national concern. Despite the intensive efforts that have been made in this area, there remains a lack of adequate information about the neurochemical mechanisms that mediate cocaine’s behavioral effects and abuse liability. 1 Selective, pharmacologically relevantbinding sites for [3H] cocaine have been identified in striatal tissue of ro-dents, 2" 5 nonhuman primates, 6 and humans. 7 These sites are associated with the monoamine uptake system and display properties characteristic of a pharmacological re-ceptor. Specifically, the sites bind [3H] cocaine saturably and reversibly, 8, 9 they display stereoselectivity for (-)-cocaine versus its enantiomer (+)-cocaine or its C-2 epimer, pseudococaine, 6 and they show a high degree of corre-spondence between the binding affinity of various cocaine analogues and their relative potencies for inhibiting dop-amine uptake6 and for producing cocaine-like behavioral effects such as behavioral stimulation, 10 intravenous self-administration, 11 and stereotypy. 2 More detailed characterization and mapping of cocaine binding sites and investigation of theirrelationship to the dopamine reuptake system has been restricted by the limitations of [3H] cocaine as a radioligand probe of the