3-甲基芬太尼衍生物构效关系及受体结合特征研究

对3-甲基芬太尼的1-苯乙基、4-N-丙酰基进行了结构改造、测定了所合成化合物的镇痛活性及部分化合物的镇痛作用持续时间、阿片受体亲和力和对阿片受体亚型的选择性。结果表明,大部分化合物均有较强的吗啡样镇痛活性,强度约为吗啡的2～180倍。所试化合物的镇痛作用持续时间比芬太尼延长6～10倍。化合物1～4的受体亲和力(IC₅₀)约为10^-7～10^-3mol。化合物13对阿片μ-受体有较高的选择性,对大鼠脑膜的λ/δ比值大于700,对小鼠脑膜的μ/δ比值为1000。

STUDIES ON STRUCTURE-ACTIVITY RELATIONSHIPS AND RECEPTOR BINDING FEATURE FOR 3-METHYLFENTANYL DERIVATIVES

Ohmefentanyl is not only a potent analgesic agent, but also a selective ligand for mu opioid receptor. In order to search for more potent analgesics, more selective ligands and long duration of analgesic action in 3-methylfentanyl derivatives, we made modifications of the 1-phenethyl and 4-N-propionyl groups in 3-methylfentanyl and synthesized 15 new compounds. The analgesic activity, duration of analgesic action, receptor binding affinity and opioid sub-receptor selectivity of some of these compounds were measured. Primary pharmacological results showed that most of the compounds in this series possessed morphine-like effects. The analgesic activities of them were about 2-180 times more potent than that of morphine. The duration of analgesic action of the tested compounds was 6-10 times longer than that of fentanyl. The receptor binding affinities (IC50) of compounds 1-4 were 10(-7)-10(-8) mol. Compound 13 displayed the best binding selectivity on mu opioid receptor site with ratio mu/delta greater than 700 in rat brain membrane and mu/delta = 1000 in mouse brain membrane. The new compound may be proposed as a useful tool in studying the opioid receptor. According to the result of equations in reference 11, compounds 7-14 were designed and prepared. The observed log 1/c values of them were much closer to the calculated values.