多位点修饰内吗啡肽及其类似物的构效关系研究
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摘要
阿片样肽是最早在神经系统中被确认的神经肽类物质,类阿片及阿片受体广泛分布于哺乳动物的中枢神经系统和外周组织。植物性阿片制剂吗啡在临床上应用于缓解急性疼痛,但是吗啡在产生镇痛作用的同时也伴随着许多的副作用,如呼吸抑制、便秘、心率过缓、血压降低以及容易成瘾产生耐受等,μ-阿片受体系统是寻找新型镇痛药物的重要靶点,内吗啡肽-1和2是对μ-阿片受体具有高亲和性和选择性的内源性阿片肽激动剂,它们同吗啡一样在较低剂量时对急性疼痛有很强的镇痛作用,同时在镇痛剂量条件下缺少部分吗啡样副作用,这就使得内吗啡肽取代吗啡成为新型镇痛药物成为可能,然而内吗啡肽镇痛作用持续时间短,体内快速被酶降解(氨肽酶及二肽基肽酶Ⅳ),通过血脑屏障到达中枢的能力差以及口服无效等缺点也大大限制了其在临床上的应用。因此本文通过对内吗啡肽加以修饰改造希望寻找有强效镇痛作用且其抗酶解能力强,持续作用时间长,副作用低的新型镇痛药物模型。
本论文将非天然氨基酸或二肽片段(Sar,D-Ala-Gly,Phg,Hfe)引入到EM-1的2和3位,且将其4位全部用D-Val4-NH-Bzl取代,通过经典液相法合成了四个EM-1的类似物并对它们的生理和药理学活性进行了检定,包括受体亲和实验,离体生物学活性检定,酶解稳定性以及在体镇痛活性的测定。我们发现所有类似物酶解稳定性都比EM-1高,只有类似物1[Sar2,D-Val4-NH-Bzl]EM-1的μ-阿片受体的亲和活性,离体生物学活性以及镇痛活性效能均比EM-1高；类似物2对μ-阿片受体亲和活性略低于EM-1,但是在所有类似物中对6-阿片受体亲和活性最高(δ)Ki达到了142nM,而EM-1的(6)Ki是5093nM,表明Tyr-D-Ala-Gly作为信息序列对配体与δ-阿片受体之间的作用产生了一定的影响,推测类似物2可能对μ和δ-阿片受体同时产生激动作用,具有双受体激动效应；其余两个类似物除了抗酶解能力均比EM-1强之外,它们对μ-阿片受体的亲和活性,离体生物学活性以及镇痛活性效能均不同程度的下降,尤其是类似物4[Phg3,D-Val4-NH-Bzl]EM-1基本上丧失了对μ-阿片受体的亲和活性和激动活性。
The opioids were among the earliest neuropeptides identified in the nervous system, opioid receptors are most abundant in the central nervous system, but have also been localized in many peripheral tissues of the mammalian organism. Centrally acting plant opiates, such as morphine, are usually used analgesics for relief of the severe pain, but their usefulness is confined by a number of well-known side effects, including respiratory depression, constipation, bradycardia, hypotension, tolerance and physical dependence and so on. Theμ-opioid receptor system is a significant target in the search for novel analgesics. Endomorphin-1 and 2 are two potent and hinghly selectiveμ-opioid receptor agonists, simultaneously they could show a strong ananlgesic activity in acute pain similar to that of morphine even at low doses, but endomorphins are thought to inhibit pain without some of the undesirde side effects of plant opiates. It is possible that endomorphins instead of morphine in the development of novel analgesics. However, endomorphins still suffers from serious limitations including short duration of action, lack of activity after oral administration, relative inability to cross the blood-brain barrier (BBB) into the central nervous system (CNS) and rapidly degradation by individual enzymes (such as dipeptidyl peptidase IV and aminopeptidases). Therefore, we hope to search novel analgesics which possess long duration of action, good metabolic stability without side effects, based various modification on endomorphins.
In this paper, we introduced unnatural amino aid and dipeptide fragment (Sar, D-Ala-Gly, Phg, Hfe) into posotion 2 and 3 of endomorphin-1, which C-terminal was substituted by D-Val4-NH-Bzl. Four analogs of EM-1 were synthesized by classic solution-phase method, and their physiological and pharmacological activities were determined, including receptor binding affinity and bioassay activity, isolated tissue assays and in vivo assays. We found that all of the analogs exhibited increased in vitro metabolic stability to EM-1 in mouse brain homogenate. Only analogs 1 ([Sar2, D-Val4-NH-Bzl](EM-1) showed higher affinity and agonist activity toμ-opioid receptor and increased in antinociceptive activity to that of EM-1. Analogs 2 had a less lower affinity and agonist activity toμ-opioid receptor compared with that of EM-1, however, Analogs 2 exhibited aδ-opioid receptor affinity 36-fold higher than that of EM-1, it suggested that Tyr-D-Ala-Gly is important toδ-opioid receptor ligand as "message sequence". We supposed that analogs 2 isμ/δ-opioid receptor agonist with bifunctional activities. The other two analogs all decreased in affinity and antinociceptive activity. Particularly analogs 4 exhibited significantly low affinity and agonist activity toμ-opioid receptor.
本论文将非天然氨基酸或二肽片段(Sar,D-Ala-Gly,Phg,Hfe)引入到EM-1的2和3位,且将其4位全部用D-Val4-NH-Bzl取代,通过经典液相法合成了四个EM-1的类似物并对它们的生理和药理学活性进行了检定,包括受体亲和实验,离体生物学活性检定,酶解稳定性以及在体镇痛活性的测定。我们发现所有类似物酶解稳定性都比EM-1高,只有类似物1[Sar2,D-Val4-NH-Bzl]EM-1的μ-阿片受体的亲和活性,离体生物学活性以及镇痛活性效能均比EM-1高；类似物2对μ-阿片受体亲和活性略低于EM-1,但是在所有类似物中对6-阿片受体亲和活性最高(δ)Ki达到了142nM,而EM-1的(6)Ki是5093nM,表明Tyr-D-Ala-Gly作为信息序列对配体与δ-阿片受体之间的作用产生了一定的影响,推测类似物2可能对μ和δ-阿片受体同时产生激动作用,具有双受体激动效应；其余两个类似物除了抗酶解能力均比EM-1强之外,它们对μ-阿片受体的亲和活性,离体生物学活性以及镇痛活性效能均不同程度的下降,尤其是类似物4[Phg3,D-Val4-NH-Bzl]EM-1基本上丧失了对μ-阿片受体的亲和活性和激动活性。
The opioids were among the earliest neuropeptides identified in the nervous system, opioid receptors are most abundant in the central nervous system, but have also been localized in many peripheral tissues of the mammalian organism. Centrally acting plant opiates, such as morphine, are usually used analgesics for relief of the severe pain, but their usefulness is confined by a number of well-known side effects, including respiratory depression, constipation, bradycardia, hypotension, tolerance and physical dependence and so on. Theμ-opioid receptor system is a significant target in the search for novel analgesics. Endomorphin-1 and 2 are two potent and hinghly selectiveμ-opioid receptor agonists, simultaneously they could show a strong ananlgesic activity in acute pain similar to that of morphine even at low doses, but endomorphins are thought to inhibit pain without some of the undesirde side effects of plant opiates. It is possible that endomorphins instead of morphine in the development of novel analgesics. However, endomorphins still suffers from serious limitations including short duration of action, lack of activity after oral administration, relative inability to cross the blood-brain barrier (BBB) into the central nervous system (CNS) and rapidly degradation by individual enzymes (such as dipeptidyl peptidase IV and aminopeptidases). Therefore, we hope to search novel analgesics which possess long duration of action, good metabolic stability without side effects, based various modification on endomorphins.
In this paper, we introduced unnatural amino aid and dipeptide fragment (Sar, D-Ala-Gly, Phg, Hfe) into posotion 2 and 3 of endomorphin-1, which C-terminal was substituted by D-Val4-NH-Bzl. Four analogs of EM-1 were synthesized by classic solution-phase method, and their physiological and pharmacological activities were determined, including receptor binding affinity and bioassay activity, isolated tissue assays and in vivo assays. We found that all of the analogs exhibited increased in vitro metabolic stability to EM-1 in mouse brain homogenate. Only analogs 1 ([Sar2, D-Val4-NH-Bzl](EM-1) showed higher affinity and agonist activity toμ-opioid receptor and increased in antinociceptive activity to that of EM-1. Analogs 2 had a less lower affinity and agonist activity toμ-opioid receptor compared with that of EM-1, however, Analogs 2 exhibited aδ-opioid receptor affinity 36-fold higher than that of EM-1, it suggested that Tyr-D-Ala-Gly is important toδ-opioid receptor ligand as "message sequence". We supposed that analogs 2 isμ/δ-opioid receptor agonist with bifunctional activities. The other two analogs all decreased in affinity and antinociceptive activity. Particularly analogs 4 exhibited significantly low affinity and agonist activity toμ-opioid receptor.
引文
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