新型四氫異喹啉μ/κ-鴉片受體促效劑之研發

Discovery of novel tetrahydroisoquinoline-based μ/κ opioid receptor agonists

陳聖仁(Shen-Ren Chen)

指導教授 ： 黎耀基 ； 翁紹華

國立清華大學/生命科學院/生物科技研究所/碩士(2015年)

https://doi.org/10.6843/NTHU.2015.00470

摘要

鴉片類藥物包含嗎啡主要作用於μ-鴉片受體，其具有止痛效果卻也伴隨其他副作用。文獻報導指出，當藥物同時具有μ-鴉片受體促效劑與κ-鴉片受體促效劑兩種性質或是μ-鴉片受體促效劑與δ-鴉片受體拮抗劑兩種性質時，能降低副作用。本論文自高速藥物篩選系統篩選出具有μ-鴉片受體促效劑活性的四氫異喹啉基化合物4後，針對苯磺醯基區塊與環己醯基區塊進行化學結構修飾修飾，並探討其結構與生物活性關係，最終得到強效之活性化合物21、51‒55、58、59、63、64、66和68‒71。此15個化合物並進行HTRF環腺苷酸檢測，測試化合物個別影響表現μ、κ和δ-鴉片受體之人類胚胎腎臟細胞的腺苷酸環化酶之活性。其中，化合物21、69‒71對表現μ和κ-鴉片受體之人類胚胎腎臟細胞的腺苷酸環化酶具有部分或良好之抑制活性，亦即化合物21、69‒71可活化μ-鴉片受體與κ-鴉片受體。接著進行化合物21和69‒71之小鼠閃尾試驗，以驗證其止痛效果。在快速篩選實驗中，化合物69在低劑量(3 mg/kg)下具有止痛效果，然而化合物21、70與71在高劑量下(20 mg/kg)表現出毒性。

關鍵字

μ-鴉片受體促效劑 ； 結構與生物活性關係

並列摘要

Opioid drugs, including morphine, primarily act on μ-opioid receptors, produce antinociceotive effect with some unacceptable side effects. Recent studies indicated that drugs possess μ/κ-opioid receptor dual agonism or the dual function of μ-opioid receptor agonism/δ-opioid receptor antagonism functional activity could reduce side effects. This study described the identification of the tetrahydroisoquinoline compounds 4 as a μ-opioid receptor agonist by high-throughput screening. The consequent chemical structural modification of the benzenesulfonyl and cyclohexanecarbonyl moieties for the structure-activity relationship study. Finally, a number of potent these compounds 21、51‒55、58、59、63、64、66、68‒71 were designed and synthesized, and ability of new compounds in affecting forskoline-stimulated adenylyl cyclase activity in HEK293 cells stably and expressing the μ-、κ- and δ-opioid receptors, respectively. In which compounds 21 and 69‒71 displayed partial to excellent inhibitory activities against adenylyl cyclase in HEK293 cells stably expressing μ- and κ- opioid receptors, respectively. In other words, compounds 21 and 69‒71 can activate both μ- and κ-opioid receptors. The compound 21 and 69‒71 were carried out quick tail-flick tests in mice to verify their analgesic effect. Among them, compound 69 demonstrated medium analgesic effect at a low dosage (3 mg/kg), however, compounds 21, 70 and 71 exhibited toxicity at a high dosage (20 mg/kg).

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