Exploiting the Power of Stereochemistry in Drug Action: 3-[(2S,6S,11S)-8-Hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide as Potent Sigma-1 Receptor Antagonist.,ACS Chemical Neuroscience

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Exploiting the Power of Stereochemistry in Drug Action: 3-[(2S,6S,11S)-8-Hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide as Potent Sigma-1 Receptor Antagonist.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-03-23 , DOI: 10.1021/acschemneuro.9b00688
Rita Turnaturi ₁ , Lorella Pasquinucci ₁ , Santina Chiechio _{2,

3} , Margherita Grasso _{2,

3} , Agostino Marrazzo ₁ , Emanuele Amata ₁ , Maria Dichiara ₁ , Orazio Prezzavento ₁ , Carmela Parenti ₂

Affiliation

(+)-(2S,6S,11S)- and (−)-(2R,6R,11R)-Benzomorphan derivatives have a different binding affinity for sigma-1 (σ1R) and opioid receptors, respectively. In this study, we describe the synthesis of the (+)-enantiomer [(+)-LP1] of the benzomorphan MOR agonist/DOR antagonist LP1 [(−)-LP1]. The binding affinity of both (+)-LP1 and (−)-LP1 for σ1R and sigma-2 receptor (σ2R) was tested. Moreover, (+)-LP1 opioid receptor binding affinity was also investigated. Finally, (+)-LP1 was tested in a mouse model of inflammatory pain. Our results showed a nanomolar σ1R and binding affinity for (+)-LP1. Both (+)-LP1 and (−)-LP1 elicited a significant analgesic effect in a formalin test. Differently from (−)-LP1, the analgesic effect of (+)-LP1 was not reversed by naloxone, suggesting a σ1R antagonist profile. Furthermore, σ1R agonist PRE-084 was able to unmask the σ1R antagonistic component of the benzomorphan compound. (+)-LP1 could constitute an useful lead compound to develop new analgesics based on mechanisms of action alternative to opioid receptor activation.

中文翻译：

利用立体化学在药物作用中的力量：3-[(2S,6S,11S)-8-羟基-6,11-二甲基-1,4,5,6-四氢-2,6-亚甲基-3-苯并佐星- 3(2H)-yl]-N-苯基丙酰胺作为有效的 Sigma-1 受体拮抗剂。

(+)-(2 S ,6 S ,11 S )- 和 (−)-(2 R ,6 R ,11 R )-苯并吗喃衍生物分别对 sigma-1 (σ1R) 和阿片受体有不同的结合亲和力。在本研究中，我们描述了苯并吗啡烷 MOR 激动剂/DOR 拮抗剂 LP1 [(−)-LP1] 的 (+)-对映体 [(+)-LP1] 的合成。测试了 (+)-LP1 和 (−)-LP1 对 σ1R 和 sigma-2 受体 (σ2R) 的结合亲和力。此外，还研究了 (+)-LP1 阿片受体结合亲和力。最后，(+)-LP1 在小鼠炎性疼痛模型中进行了测试。我们的结果显示了纳摩尔 σ1R 和 (+)-LP1 的结合亲和力。 (+)-LP1 和 (−)-LP1 在福尔马林试验中均产生显着的镇痛效果。与 (−)-LP1 不同的是，(+)-LP1 的镇痛作用不会被纳洛酮逆转，表明具有 σ1R 拮抗剂特性。此外，σ1R 激动剂 PRE-084 能够揭示苯并吗喃化合物的 σ1R 拮抗成分。 (+)-LP1 可以构成一种有用的先导化合物，用于开发基于阿片受体激活替代作用机制的新型镇痛药。

更新日期：2020-03-24

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