Methoxycarbonyl-1-phenyl-2-cyclopropylmethyl based derivatives cis-(+)-1a [cis-(+)-MR200], cis-(−)-1a [cis-(−)-MR201], and trans-(±)-1a [trans-(±)-MR204], have been identified as new potent sigma (σ) receptor ligands. In the present paper, novel enantiomerically pure analogues were synthesized and optimized for their σ receptor affinity and selectivity. Docking studies rationalized the results obtained in the radioligand binding assay. Absolute stereochemistry was unequivocally established by X-ray analysis of precursor trans-(+)-5a as camphorsulfonyl derivative 9. The most promising compound, trans-(+)-1d, showed remarkable selectivity over a panel of more than 15 receptors as well as good chemical and enzymatic stability in human plasma. An in vivo evaluation evidenced that trans-(+)-1d, in contrast to trans-(−)-1d, cis-(+)-1d, or cis-(−)-1d, which behave as σ₁ antagonists, exhibited a σ₁ agonist profile. These data clearly demonstrated that compound trans-(+)-1d, due to its σ₁ agonist activity and favorable receptor selectivity and stability, provided an useful tool for the study of σ₁ receptors.

中文翻译：

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（+）-甲基（1 R，2 S）-2-{[4-（4-氯苯基）-4-羟基哌啶-1-基]甲基} -1-苯基环丙烷羧酸酯[（+）-MR200]衍生物和选择性西格玛受体配体：立体化学和药理特性

基于甲氧羰基-1-苯基-2-环丙基甲基的衍生物cis -（+）- 1a [ cis -（+）-MR200]，cis -（-）- 1a [ cis -（-）-MR201]和反式-（± ） - 1A [反式- （±）-MR204]，已被确定为新的有效西格玛（σ）受体配体。在本文中，合成了新颖的对映体纯类似物，并针对其σ受体亲和力和选择性进行了优化。对接研究使在放射性配体结合测定中获得的结果合理化。通过对前体反式-（+）- 5a作为樟脑磺酰基衍生物的X射线分析明确建立了绝对立体化学9。最有前途的化合物反式（（+）- 1d）在超过15种受体上显示出显着的选择性，并在人血浆中具有良好的化学和酶稳定性。体内评价证明该反式- （+） - 1D，而相比之下，反式- （ - ） - 1D，顺式- （+） - 1D，或顺式- （ - ） - 1D，其表现为σ ₁拮抗剂，表现出一个σ ₁激动剂曲线。这些数据清楚地表明，化合物反式- （+） - 1D，由于其σ ₁激动剂活性和良好的受体选择性和稳定性，提供了一种用于σ研究的一个有用的工具₁受体。