Department of Drug Sciences, Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
Department of Drug Sciences, Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
ACS Chem Neurosci. 2020 Apr 1;11(7):999-1005. doi: 10.1021/acschemneuro.9b00688. Epub 2020 Mar 23.
(+)-(2,6,11)- and (-)-(2,6,11)-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.
(+)-(2,6,11)-和(-)-(2,6,11)-苯并吗啡烷衍生物分别对sigma-1（σ1R）和阿片受体具有不同的结合亲和力。在这项研究中，我们描述了苯并吗啡烷 MOR 激动剂/DOR 拮抗剂 LP1 的（+）对映体[(+)-LP1]的合成[（-）-LP1]。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 对阿片受体的结合亲和力。最后，在炎性疼痛的小鼠模型中测试了（+）-LP1。我们的结果显示（+）-LP1 对σ1R 具有纳摩尔亲和力。（+）-LP1 和（-）-LP1 在福马林试验中均表现出显著的镇痛作用。与（-）-LP1 不同，纳洛酮不能逆转（+）-LP1 的镇痛作用，提示其具有σ1R 拮抗剂特征。此外，σ1R 激动剂 PRE-084 能够揭示苯并吗啡烷化合物的 σ1R 拮抗成分。（+）-LP1 可能成为开发基于与阿片受体激活替代作用机制的新型镇痛药的有用先导化合物。
