原小蘗鹼型生物鹼衍生物鎮靜及鎮痛活性之評估

Sedative and Analgesic Activities of Protoberberine Type Alkaloid Derivatives

本研究以palmatine（Ⅰ）及tetrahydropalmatine（Ⅱ）為起始物質，利用化學合成方法合成：7, 8-dihydropalmatine（Ⅲ）、7, 8-dihydropalmatine methyliodide（Ⅳ）、tetrahydropalmatine methyl iodide（Ⅴ）、palmatinephenolbetaine Ⅵ）、 2,3,9,10-tetramethoxy-8,14-cycloberbin-13-one（Ⅶ）、1-（α-naphthyl）-3,4-dihydroisoquinoline vinyl diacetate（Ⅷ）、1-spiroisoquinoline（Ⅸ）等九個化合物，並進行其鎮靜及鎮痛之藥理活性之評估。實驗結果顯示，所有化合物對腹腔注射（i.p.）pentobarbital（50 mg/kg）所誘發之睡眠時間都具有延長作用，在1 mg/kg, i.p.時以化合物I效果最好；而在1%醋酸（0.1 ml/10g, i.p.）誘發扭體反應之鎮痛實驗中，所有化合物在1 mg/kg 下均有相似之鎮痛作用，但以化合物Ⅰ、Ⅱ、Ⅲ、Ⅳ及Ⅴ等五個化合物在腹腔給予10 mg/kg 時可以完全抑制醋酸所引起之小鼠扭體反應。綜合上述化學與藥理二方面之實驗結果，可推得下列兩個結論：（1）保存母核四個環的完整很重要；當母核上的第B、C兩環分別裂開但仍保持環型三級胺時其鎮靜及鎮痛之藥理活性減弱。（2）在母核氮上具甲基形成四級銨鹽時，會使其鎮靜之藥理活性減弱，但對鎮痛作用沒有影響。

Our studies used palamtine (Ⅰ) and tetrahydropalmatine (Ⅱ) as starting materials and synthesized seven different derivatives as follows: 7, 8-dihydropalmatine (Ⅲ), 7, 8-dihydropalmatine methyl iodide (Ⅳ), tertrahydropalmatine methyl iodide (Ⅴ), palmatinephenolbetaine (Ⅵ), 2, 3,9,10-tetramethoxy-8,14-cyclohberbin-13-one (Ⅶ), 1-(α-naphthyl)-3, 4-dihydroisoquinoline vinyl diacetate (Ⅷ), and lspiroisoquinoline (Ⅸ). They were evaluated for their sedative and analgesic activities. Results showed that they all lengthened the sleeping time which induced by pentobarbital (50 mg/kg, i.p.) and the most potent one is palmatine (1 mg/kg; i.p.). The writhing response by injection of 1% acetic acid (0.1 ml/10g) was completed abolished when giving compound Ⅰ, Ⅱ, Ⅲ, Ⅳ, and Ⅴ at the dose of 10 mg/kg (i.p.), respectively. Comparison among these derivatives the following two conclusions were obtained: (1) It is important that the parent four ring skeleton is retained, effects diminished when the ring structure was opened. (2) Methylation of nitrogen on the parent nucleus to quaternary ammonium salt would reduce its activity.