Department of Medicinal Chemistry, AstraZeneca R&D Montreal, 7171 Frederick-Banting, Saint-Laurent, Quebec, Canada H4S 1Z9.
Bioorg Med Chem Lett. 2012 Jun 15;22(12):3884-9. doi: 10.1016/j.bmcl.2012.04.128. Epub 2012 May 4.
Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.
大麻素 CB1 受体激动剂在啮齿动物和人类中表现出强大的镇痛作用，但由于中枢介导的副作用，它们作为镇痛药物的临床应用往往受到限制。本文报道了 N-甲基-3-(四氢-2H-吡喃-4-基)-2,3,4,9-四氢-1H-咔唑-6-甲酰胺的制备，作为一类具有吸引力的物理化学性质的新型 hCB1/hCB2 双重激动剂。具体而言，(R)-N,9-二甲基-N-(4-(甲氨基)-4-氧代丁基)-3-(四氢-2H-吡喃-4-基)-2,3,4,9-四氢-1H-咔唑-6-甲酰胺，表现出极低的中枢神经系统穿透水平（大鼠 Cbr/Cplasma=0.005 或 0.5%），并且在药效学测试中没有中枢神经系统副作用。
