Pronounced pharmacological differences arising from minor structural changes in conformationally defined amphetamine analogues. Comparative evaluation of endo- and exo-2-amino- and endo- and exo-2-(methylamino)benzobicyclo[2.2.1]heptene and -benzobicylco[2.2.2]octene analogues. Conformationally defi
Pronounced pharmacological differences arising from minor structural changes in conformationally defined amphetamine analogues. Comparative evaluation of endo- and exo-2-amino- and endo- and exo-2-(methylamino)benzobicyclo[2.2.1]heptene and -benzobicylco[2.2.2]octene analogues. Conformationally defi
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显着的药理学差异源于构象定义的安非他明类似物的微小结构变化。
DOI：
10.1021/jm00180a006
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发表时间：
1980
影响因子：
7.3
通讯作者：
J. A. Ruth
中科院分区：
文献类型：
--
作者：
G. L. Grunewald;T. Reitz;A. Hallett;C. Rutledge;S. Vollmer;J. Archuleta;J. A. Ruth
安非他明的构象确定的类似物外-（3a）和内-2-氨基苯并双环[2.2. 1]庚烯（4a）和甲基苯丙胺，外-（3b）和内-2-（甲氨基）苯并双环[2.2.合成了庚烯（4 b），并通过核磁共振分析证实了它们的立体化学归属。将苯并降冰片烯-2-酮（7）转化为其肟（8），然后还原为4a。胺4 b由7通过用甲胺和NaBHgCN还原胺化制备。胺3a通过还原由苯并降冰片二烯和叠氮化汞形成的叠氮化物5而获得。将3a甲酰化，然后氢化物还原，得到胺3b。评价了这些化合物抑制[3 H]去甲肾上腺素（[3 H] NE）进入切碎的大脑皮层和心房组织、增加小鼠运动活性和增加离体大鼠心房搏动率的能力。药理学操作进行了不同的NE释放池从主要囊泡到主要囊外的性质。将数据与先前报道的密切相关的安非他明类似物外-（Ia）和内-2-氨基苯并双环[2.2. 2]辛烯（2a）和甲基苯丙胺类似物外-（1b）和内-2-（甲氨基）苯并双环[2.2.1]。2]辛烯（2b）。正如在[2.2.]中发现的构象限制的gauche类似物2a和2b。2]环系统，endo [2.2. 1]类似物（4a，B）的活性始终低于反周面（exo）类似物。然而，在exo类似物（3a，B）中，从exo的亚乙基桥上除去一个亚甲基单元[2.2. 2]环系统导致明显的药理学差异。虽然3b是等效的甲基苯丙胺释放[3 H] NE从extravesicular storagesites测量的生化方法（示踪剂研究），释放extravesicular NE测量的生理方法（孤立的心房，运动活动）显然是掩盖了一个非特异性的化合物诱导的抑制作用。[2.2]未观察到这些复杂因素。2]模拟磅此外，虽然Ia和Ib均显示对[3 H] NE的可释放池的区室化的敏感性，但3a显示敏感性丧失（可能通过单胺氧化酶抑制）。由于这些药理学差异发生在相对较小的结构修改，应小心行使在利用这些化合物作为工具，用于评估构象的偏好时，药理学评价休息时的生理活力的效应membranes.We最近已经证明了构象prefections为安非他明诱导的抑制[3 H]-去甲肾上腺素（[3 H] NE）摄取1和释放1，通过利用2-氨基苯并双环[2.2. 2]辛烯和作为甲基苯丙胺类似物的2-（甲基氨基）苯并双环[2.2. 2]辛烯（图I）。这种方法的基本原理是基于这种环系统提供的安非他明（或甲基安非他明）旋转异构体的出色空间近似。2-甲胺衍生物的内异构体和外异构体分别提供了甲基苯丙胺的thegauche和完全扩展（见图I）构象的优良无应变模型，通过分子轨道计算3和X射线晶体学确定键级、角度和距离的扰动最小。4药理实验结果表明，
The conformationally defined analogues of amphetamine, exo-(3a) and endo-2-aminobenzobicyclo [2.2. 1] heptene (4a), and methamphetamine, exo-(3b) and endo-2-(methylamino) benzobicyclo [2.2. Ijheptene (4b), were synthesized and their stereochemical assignments confirmed by NMR analysis. Benzonorbornen-2-one (7) was converted to its oxime (8), followed by reduction to 4a. Amine 4b was produced from 7 by reductive amination with methylamine and NaBHgCN. Amine 3a was obtained by reduction of azide 5, formed from benzonorbornadiene and mercuric azide. Formylation of 3a, followed by hydride reduction, gave amine 3b. These compounds were evaluated for their ability to inhibit the uptake of [3H] norepinephrine ([3H] NE) into chopped cerebral cortex and atrial tissue, to increase locomotor activity in mice, and to increase the beating rate of isolated rat atria. Pharmacological manipulations were performed to vary the releasable pool of NE fromprimarily vesicular to primarily extravesicular in nature. The data were compared to those previously reported for the closely related amphetamine analogues exo-(la) and endo-2-aminobenzobicyclo [2.2. 2] octene (2a) and methamphetamine analogues exo-(lb) and endo-2-(methylamino) benzobicyclo [2.2. 2] octene (2b). As was found for the conformationally restricted gauche analogues 2a and 2b in the [2.2. 2] ring system, the endo [2.2. 1] analogues (4a, b) were consistently less active than the trans antiperiplanar (exo) analogues. However, in the exo analogues (3a, b) removal of one methylene unit from the ethylene bridge of the exo [2.2. 2] ring system resulted in pronounced pharmacological differences. While 3b was equipotent with methamphetamine in releasing [3H] NE from extravesicular storagesites as measured by biochemical methods (tracer studies), release of extravesicular NE as measured by physiological methods (isolated atria, locomotor activity) was apparently masked by a nonspecific depressant effect induced by the compound. These complicating factors were not observed for the [2.2. 2] analogue lb. Also, while both la and lb showed a sensitivity to compartmentation of the releasable pool of [3H] NE, 3a showed a loss of sensitivity (possibly through monoamineoxidase inhibition). Since these pharmacological differences occurred upon relatively minor structural modifications, care should be exercised in utilizing such compounds as tools for assessing conformational preferences when the pharmacological evaluations employed rest upon physiological viability of effector membranes.We have recently demonstrated conformational pref-erences for the amphetamine-induced inhibition of [3H]-norepinephrine ([3H] NE) uptake1 and for the release1, 2 of previously accumulated [3H] NE from adrenergic nerve terminals of rat brain and rat atria by utilizing as con-formationally defined amphetamine analogues the exo (la) and endo (2a) isomers of 2-aminobenzobicyclo [2.2. 2] octene and as methamphetamine analogues the exo (lb) and endo (2b) isomers of 2-(methylamino) benzobicyclo [2.2. 2] octene (Chart I). The rationale for this approach was based upon the excellent spatial approximations of amphetamine (or methamphetamine) rotamers afforded by this ring system. The endo and exo isomers of the 2-methylamine derivative provide excellent strain-free models of thegauche and fully extended (see Chart I) conformations, respectively, of methamphetamine, with minimal perturbation of bond orders, angles, and distances as determined by molecular orbital calculations3 and X-ray crystallography. 4 The pharmacological results indicated that, while the fully