Cheng C Y, Hsin L W, Tsai M C, Schmidt W K, Smith C, Tam S W
School of Pharmacy and Pharmacological Institute, College of Medicine, National Taiwan University, Taipei.
J Med Chem. 1994 Sep 16;37(19):3121-7. doi: 10.1021/jm00045a017.
3-(Cyclopropylmethyl)-9-hydroxy-7-oxo-2,3,4,4a alpha,5,6,7,7a alpha- octahydro-1H-benzofuro[3,2-e]isoquinoline (4b) containing the ACNO ring system of morphine and a 7-keto function on ring C has been synthesized and found to possess potent PQW (ED50 = 0.15 mg/kg sc) and anti-Straub tail (ED50 = 0.02 mg/kg sc) activity. As compared to its 7-deoxy analog 1b, introduction of the 7-keto group did not significantly affect binding to any of the three opioid receptors (mu, kappa, and delta), but caused a 34-fold reduction in sigma-binding, suggesting reduced propensity to induce psychotomimetic effects. The C/D cis isomer of 4b (4c) was much less potent at the three opioid receptors, while displaying a slight increase in sigma affinity. Both 7-hydroxy derivatives 4e and 4f were active in anti-Straub tail assay (ED50 < or = 0.8 mg/kg sc), but only the alpha-isomer 4e demonstrated analgesic activity (PQW ED50 = 0.37 mg/kg sc) in the dose range tested. In guinea pig ileum preparations, 4e was characterized as a selective full agonist at the kappa opioid receptor (IC50 = 2.8 nM); while its beta-isomer 4f was a partial agonist (78% at 1 microM), with antagonist activity observed at both mu- and kappa-opioid receptors.
3-(环丙基甲基)-9-羟基-7-氧代-2,3,4,4aα,5,6,7,7aα-八氢-1H-苯并呋喃[3,2-e]异喹啉(4b)已被合成，其含有吗啡的ACNO环系且在C环上具有7-酮功能，发现它具有强效的扭体反应抑制作用(皮下注射半数有效剂量ED50 = 0.15 mg/kg)和抗斯特劳布尾反应(皮下注射半数有效剂量ED50 = 0.02 mg/kg)活性。与它的7-脱氧类似物1b相比，引入7-酮基对与三种阿片受体(μ、κ和δ)的任何一种结合均无显著影响，但导致σ结合降低34倍，提示诱导拟精神病作用的倾向降低。4b的C/D顺式异构体(4c)在三种阿片受体上的活性低得多，同时σ亲和力略有增加。两种7-羟基衍生物4e和4f在抗斯特劳布尾反应试验中均有活性(皮下注射半数有效剂量ED50≤0.8 mg/kg)，但在测试剂量范围内只有α异构体4e表现出镇痛活性(扭体反应抑制作用皮下注射半数有效剂量ED50 = 0.37 mg/kg)。在豚鼠回肠制备物中，4e被表征为κ阿片受体的选择性完全激动剂(半数抑制浓度IC50 = 2.8 nM)；而其β异构体4f是部分激动剂(1 μM时为78%)，在μ和κ阿片受体上均观察到拮抗活性。
