Gram Scale Syntheses of (-)-Incarvillateine and Its Analogs. Discovery of Potent Analgesics for Neuropathic Pain
| Autor: | Bin Huang, Yan Song, Meiliang Wang, Xintong Wang, Yanxing Jia, Feng-Ying Zhang, Rui-Bin Su, Gang Yu, Ze-Hui Gong |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Gabapentin Analgesic Pharmacology 01 natural sciences 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine Alkaloids In vivo Incarvillateine Drug Discovery medicine Structure–activity relationship Animals Mice Inbred ICR 010405 organic chemistry Chemistry medicine.disease 0104 chemical sciences Nociception Neuropathic pain Neuralgia Monoterpenes Molecular Medicine 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 59(8) |
| ISSN: | 1520-4804 |
| Popis: | (-)-Incarvillateine (INCA) is the major antinociceptive component of Incarvillea sinensis, which has been used to treat rheumatism and relieve pain in traditional Chinese medicine. We have developed a concise and general synthetic approach for INCA, which enabled gram-scale asymmetric syntheses of (-)-INCA, (-)-incarvilline, (-)-isoincarvilline, and six other INCA analogues. The synthesis of isoincarvilline was reported for the first time. Three structurally simplified analogues of INCA were also synthesized. In vivo screening found that INCA and two structurally optimized analogues were efficacious in preventing the acetic acid-induced writhing response. Moreover, their analgesic efficacy was demonstrated in formalin induced pain model. More importantly, administration of 20 or 40 mg/kg INCA and two structurally optimized analogues showed strong analgesic effects in spared nerve injury (SNI) model, and their effective doses were lower than the current gold standard, gabapentin (100 mg/kg in this model). |
| Databáze: | OpenAIRE |
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