内吗啡肽-1衍生多肽的设计合成、生物学活性及血脑屏障通透性研究
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摘要
阿片肽一直以来用于缓解疼痛，且其镇痛机制主要通过中枢神经系统介导。1997年，从牛脑中分离出的两个对μ阿片受体(MOR)有着高亲和性和选择性的内源性阿片肽，内吗啡肽-1(EM-1，Tyr-Pro-Trp-Phe-NH_2)和内吗啡肽-2(EM-2，Tyr-Pro-Trp-Phe-NH_2)，被公认为MOR的内源性配体。它们都能产生与吗啡等效的镇痛作用而缺少部分吗啡样副作用。然而，内吗啡肽同时又具有酶解稳定性差、不易透过血脑屏障(BBB)和镇痛作用不能持久等缺点，从而限制了其在临床上的应用。改进办法之一即对其做系统改造。研究表明EM-1具有优于EM-2的治疗学特性，更适于作为新的安全镇痛药物进行开发研究，因此本研究中我们选择了EM-1为母体，旨在通过引入当前阿片肽设计中的成功化学修饰对其加以改造，希望能够提高EM-1的酶解稳定性和血脑屏障通透性，使之能够通过外周注射产生中枢介导的强效镇痛作用；通过研究不同化学修饰对EM-1理化性质以及生物学活性的影响，还将有利于我们深入理解多肽镇痛药物发挥药理学活性的必需结构，为将来基于EM-1结构的镇痛药物的发展和研究提供重要依据。
引入的化学修饰包括N-末端Tyr~1N~α胍基化修饰(阳离子化)，非天然氨基酸或二肽片段(D-Ala，Sar，D-Pro-Gly)替换L-Pro~2以及C-末端Phe芳香环对位氯化修饰。通过以上三类化学修饰的单独应用或不同组合，通过经典液相法合成了10个EM-1新型衍生多肽。我们检测了EM-1及其衍生多肽的受体结合活性，比较了不同化学修饰对多肽整体脂溶性、酶解稳定性、血浆蛋白结合、镇痛活性、跨血脑屏障转运入脑能力、小鼠结肠运动功能的调节和大鼠离体支气管上活性的影响。受体结合实验结果提示胍基化修饰和氯化修饰都不同程度地降低了EM-1与MOR的结合亲和力与选择性，同时这两种改造也导致了多肽与血浆蛋白结合的提高。所有EM-1衍生多肽在小鼠脑质膜和血清中的离体酶解稳定性较母体显著提高。通过比较各组对应衍生多肽在小鼠脑质膜和血清中的降解半衰期，发现N-末端胍基化修饰和2位非天然氨基酸替换都导致了衍生多肽抗酶解能力的显著提高，而C-末端氯化修饰对多肽的血清稳定性的提高作用显著。EM-1及其衍生多肽的正辛醇／缓冲液分配系数的比较结果表明C-末端氯化修饰确实提高了多肽的整体脂溶性，同时它还减弱了N-末端胍基化修饰引起的药物整体脂溶性的降低。2位D-Ala和D-Pro-Gly替换也可部分地导致衍生多肽脂溶性的提高，但Sar替换则没有这种作用。在所有测试多肽中，侧脑室注射GDAPC表现出最佳的镇痛效果，镇痛效力较母体提高3倍。所有衍生多肽的镇痛作用时间都较母体明显延长。静脉和皮下注射四个D-Ala~2替换的衍生多肽(HDAPC，HDADC，GDAPC，GDADC)以及氯化修饰的2位D-Pro-Gly替换的五肽(GBDPC)均可产生明显的长时程中枢介导的镇痛作用，提示可能有相对多的多肽可透过BBB进入中枢神经系统(CNS)发挥镇痛活性。给小鼠静脉注射上述五个EM-1衍生多肽，结果显示它们的在体稳定性较母体显著提高，且在脑实质中可检测到它们的存在，脑血管渗透常数K_(in)介于0．241到0．894μl／g·min之间，证明这些衍生多肽确实跨过了BBB进入大脑，从而为阐明镇痛活性分析中提出的中枢介导机制提供了重要证据。EM-1及其衍生多肽在小鼠近端及远端结肠上的在体活性与母体相似。它们都不同程度地延长了小鼠排珠时间以及抑制了标记染料在近端结肠上的推进速率，该抑制作用呈剂量依赖性，且可被纳洛酮拮抗，提示阿片受体参与了此作用。胍基化修饰更多的影响了多肽在小鼠结肠上的活性，而氯化修饰则影响不大。离体组织上的实验结果表明，吗啡、EM-1及其五个衍生多肽均能剂量依赖地诱导小鼠离体结肠纵形肌的自主收缩，纳络酮、β-FNA、河豚毒素和吲哚美辛均能显著拮抗此收缩效应。另外，它们均能浓度和频率(1，2，4 Hz)依赖地抑制电刺激(EFS)引起的大鼠离体支气管胆碱能收缩反应，且该抑制作用可被纳洛酮显著拮抗。在相同频率刺激时，EM-1的抑制作用强于等浓度的吗啡和五个衍生多肽。比较结果显示氯化修饰和胍基化修饰分别减弱和加强了多肽对大鼠支气管收缩反应的抑制作用。
Opioid peptides have been designed for the treatment of pain, and the mediation of opioid analgesia has long been thought to occur exclusively within the central nervous system (CNS). In 1997, two tetrapeptides, endomorphin (EM)-1 (Tyr~1-Pro~2-Trp~3-Phe~4-NH_2) and EM-2 (Tyr~1-Pro~2-Phe~3-Phe~4-NH_2), have been isolated from bovine frontal cortex and were reported to be the endogenous ligands to u-opioid receptors. With high affinity and selectivity for the u-opioid receptors, these two neuropeptides were found to elicit equipotent analgesia to morphine but without some of its undesirable side effects. Unfortunately, both EM-1 and EM-2 undergo metabolic degradation by peptidases. Besides, the existence of the blood-brain barrier (BBB) also limits the transit of peptides into the CNS, thus further reducing their therapeutic benefits. One solution to these problems is to design and synthesize new and improved EM analogues by chemical modification. Herein, EM-1 was chosen as the parent peptide because there were evidences that EM-1 had a more favorable therapeutic profile than EM-2 and otherμ-opioids. The aim of the present study is to make EM-1 overcome the problems of enzymatic degradation and limited entry into the CNS by systematic chemical modification, thus being able to produce analgesia after systemic administration. A clear understanding of the potential contribution of these modifications to the physicochemical properties and biological activity of EM-1 will further our knowledge of the structural requirements that is necessary for its pharmacological effects, and will provide important evidences for the development of novel analgesics based on EM-1.
Three groups of modification approaches, including N-terminal cationization by N~α-amidination on Tyr~1, unnatural amino acid (D-Ala, D-Pro and Sar) substitutions in position 2 and C-terminal chloro-halogenation, were introduced into the primary structure of EM-1. Ten EM-1 derived peptides were synthesized. Effects of each modification on enzymatic breakdown, lipophilicity and protein binding were determined and compared. For the determination of the biological activity profiles, we used a battery of test systems, including receptor binding assays, isolated tissue assays and in vivo assays. Both N-terminal cationization and C-terminal chloro-halogenation caused a decrease of affinity for the u-opioid receptor, but they increased protein binding ability of peptides. All of the synthetic peptides exhibited increased in vitro metabolic stability to the parent in both mouse brain homogenate and serum. The N~α-amidination contributed to the majority enhancement of brain stability, whereas chloro-halogenation, together with amino acid substitution in position 2, was more important for the serum stability enhancement. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by N~α-amidination, and introduction of D-Ala as well as D-Pro-Gly, but not Sar, in place of L-Pro~2, also increased the overall lipophilicity to some extent. In the antinociceptive activity test, intracerebroventricular injection of GDAPC showed the strongest analgesia among all of the peptides tested, being 3 times more potent than EM-1. In addition, all of the synthetic peptides showed an increased duration of action compared with the parent peptide. We also found that in comparison with EM-1, the four D-Ala-containing tetrapeptides and the chloro-halogenated D-Pro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon both subcutaneous and intravenous administration, indicating that more peptides might reach the CNS, eliciting greater analgesic effect. When given intravenously to mice, these five EM-1 derived peptides exhibited different pharmacokinetic properties and had significantly increased elimination half-lives compared with the parent. They showed an apparent distribution to the brain after intravenous administration, with the blood-to-brain influx rates ranging from 0.241 to 0.894μl/g·min, thus providing preliminary evidence for the central mechanism in the antinociception test. We extended to explore the pharmacological characteristics of EM-1 and its five derived peptides in mouse colon. The five EM-1 derived peptides displayed a profile similar to the parent on the mouse colon in vivo. When given centrally, they all dose-dependently inhibited colonic bead expulsion and retarded the rate of large intestinal transit in mice in a naloxone-sensitive manner. They also induced dose-dependent contraction on the isolated longitudinal muscle strips of mouse distal colon, which were significantly antagonized by naloxone,β-funaltrexamine, tetrodotoxin and indomethacin. Differences among the synthetic tetrapeptides in both in vivo and in vitro studies suggested that N-terminal cationization had a greater influence on the regulation of the colonic motor actions relative to the C-terminal halogenation. We compared the inhibitory effects of morphine and these peptides on the electrical field stimulation (EFS)-induced cholinergic bronchoconstriction in normal rats. All of the drugs tested inhibited the EFS-induced cholinergic constriction in rat isolated bronchus in a concentration- and frequency-dependent and naloxone-sensitive manner. The inhibitory effect of EM-1 on the EFS-induced bronchoconstriction was stronger than that of the same dose of morphine as well as the five EM-1 derived peptides at the same frequency. Our results indicated that N-terminal cationization and C-terminal halogenation showed opposite influences on the inhibitory effects of the four D-Ala-containing peptides in rat isolated bronchus.
引入的化学修饰包括N-末端Tyr~1N~α胍基化修饰(阳离子化)，非天然氨基酸或二肽片段(D-Ala，Sar，D-Pro-Gly)替换L-Pro~2以及C-末端Phe芳香环对位氯化修饰。通过以上三类化学修饰的单独应用或不同组合，通过经典液相法合成了10个EM-1新型衍生多肽。我们检测了EM-1及其衍生多肽的受体结合活性，比较了不同化学修饰对多肽整体脂溶性、酶解稳定性、血浆蛋白结合、镇痛活性、跨血脑屏障转运入脑能力、小鼠结肠运动功能的调节和大鼠离体支气管上活性的影响。受体结合实验结果提示胍基化修饰和氯化修饰都不同程度地降低了EM-1与MOR的结合亲和力与选择性，同时这两种改造也导致了多肽与血浆蛋白结合的提高。所有EM-1衍生多肽在小鼠脑质膜和血清中的离体酶解稳定性较母体显著提高。通过比较各组对应衍生多肽在小鼠脑质膜和血清中的降解半衰期，发现N-末端胍基化修饰和2位非天然氨基酸替换都导致了衍生多肽抗酶解能力的显著提高，而C-末端氯化修饰对多肽的血清稳定性的提高作用显著。EM-1及其衍生多肽的正辛醇／缓冲液分配系数的比较结果表明C-末端氯化修饰确实提高了多肽的整体脂溶性，同时它还减弱了N-末端胍基化修饰引起的药物整体脂溶性的降低。2位D-Ala和D-Pro-Gly替换也可部分地导致衍生多肽脂溶性的提高，但Sar替换则没有这种作用。在所有测试多肽中，侧脑室注射GDAPC表现出最佳的镇痛效果，镇痛效力较母体提高3倍。所有衍生多肽的镇痛作用时间都较母体明显延长。静脉和皮下注射四个D-Ala~2替换的衍生多肽(HDAPC，HDADC，GDAPC，GDADC)以及氯化修饰的2位D-Pro-Gly替换的五肽(GBDPC)均可产生明显的长时程中枢介导的镇痛作用，提示可能有相对多的多肽可透过BBB进入中枢神经系统(CNS)发挥镇痛活性。给小鼠静脉注射上述五个EM-1衍生多肽，结果显示它们的在体稳定性较母体显著提高，且在脑实质中可检测到它们的存在，脑血管渗透常数K_(in)介于0．241到0．894μl／g·min之间，证明这些衍生多肽确实跨过了BBB进入大脑，从而为阐明镇痛活性分析中提出的中枢介导机制提供了重要证据。EM-1及其衍生多肽在小鼠近端及远端结肠上的在体活性与母体相似。它们都不同程度地延长了小鼠排珠时间以及抑制了标记染料在近端结肠上的推进速率，该抑制作用呈剂量依赖性，且可被纳洛酮拮抗，提示阿片受体参与了此作用。胍基化修饰更多的影响了多肽在小鼠结肠上的活性，而氯化修饰则影响不大。离体组织上的实验结果表明，吗啡、EM-1及其五个衍生多肽均能剂量依赖地诱导小鼠离体结肠纵形肌的自主收缩，纳络酮、β-FNA、河豚毒素和吲哚美辛均能显著拮抗此收缩效应。另外，它们均能浓度和频率(1，2，4 Hz)依赖地抑制电刺激(EFS)引起的大鼠离体支气管胆碱能收缩反应，且该抑制作用可被纳洛酮显著拮抗。在相同频率刺激时，EM-1的抑制作用强于等浓度的吗啡和五个衍生多肽。比较结果显示氯化修饰和胍基化修饰分别减弱和加强了多肽对大鼠支气管收缩反应的抑制作用。
Opioid peptides have been designed for the treatment of pain, and the mediation of opioid analgesia has long been thought to occur exclusively within the central nervous system (CNS). In 1997, two tetrapeptides, endomorphin (EM)-1 (Tyr~1-Pro~2-Trp~3-Phe~4-NH_2) and EM-2 (Tyr~1-Pro~2-Phe~3-Phe~4-NH_2), have been isolated from bovine frontal cortex and were reported to be the endogenous ligands to u-opioid receptors. With high affinity and selectivity for the u-opioid receptors, these two neuropeptides were found to elicit equipotent analgesia to morphine but without some of its undesirable side effects. Unfortunately, both EM-1 and EM-2 undergo metabolic degradation by peptidases. Besides, the existence of the blood-brain barrier (BBB) also limits the transit of peptides into the CNS, thus further reducing their therapeutic benefits. One solution to these problems is to design and synthesize new and improved EM analogues by chemical modification. Herein, EM-1 was chosen as the parent peptide because there were evidences that EM-1 had a more favorable therapeutic profile than EM-2 and otherμ-opioids. The aim of the present study is to make EM-1 overcome the problems of enzymatic degradation and limited entry into the CNS by systematic chemical modification, thus being able to produce analgesia after systemic administration. A clear understanding of the potential contribution of these modifications to the physicochemical properties and biological activity of EM-1 will further our knowledge of the structural requirements that is necessary for its pharmacological effects, and will provide important evidences for the development of novel analgesics based on EM-1.
Three groups of modification approaches, including N-terminal cationization by N~α-amidination on Tyr~1, unnatural amino acid (D-Ala, D-Pro and Sar) substitutions in position 2 and C-terminal chloro-halogenation, were introduced into the primary structure of EM-1. Ten EM-1 derived peptides were synthesized. Effects of each modification on enzymatic breakdown, lipophilicity and protein binding were determined and compared. For the determination of the biological activity profiles, we used a battery of test systems, including receptor binding assays, isolated tissue assays and in vivo assays. Both N-terminal cationization and C-terminal chloro-halogenation caused a decrease of affinity for the u-opioid receptor, but they increased protein binding ability of peptides. All of the synthetic peptides exhibited increased in vitro metabolic stability to the parent in both mouse brain homogenate and serum. The N~α-amidination contributed to the majority enhancement of brain stability, whereas chloro-halogenation, together with amino acid substitution in position 2, was more important for the serum stability enhancement. Determination of the octanol/buffer coefficient revealed that chloro-halogenation did compromise the decreased lipophilicity caused by N~α-amidination, and introduction of D-Ala as well as D-Pro-Gly, but not Sar, in place of L-Pro~2, also increased the overall lipophilicity to some extent. In the antinociceptive activity test, intracerebroventricular injection of GDAPC showed the strongest analgesia among all of the peptides tested, being 3 times more potent than EM-1. In addition, all of the synthetic peptides showed an increased duration of action compared with the parent peptide. We also found that in comparison with EM-1, the four D-Ala-containing tetrapeptides and the chloro-halogenated D-Pro-Gly-containing pentapeptide elicited significant and prolonged central-mediated analgesia upon both subcutaneous and intravenous administration, indicating that more peptides might reach the CNS, eliciting greater analgesic effect. When given intravenously to mice, these five EM-1 derived peptides exhibited different pharmacokinetic properties and had significantly increased elimination half-lives compared with the parent. They showed an apparent distribution to the brain after intravenous administration, with the blood-to-brain influx rates ranging from 0.241 to 0.894μl/g·min, thus providing preliminary evidence for the central mechanism in the antinociception test. We extended to explore the pharmacological characteristics of EM-1 and its five derived peptides in mouse colon. The five EM-1 derived peptides displayed a profile similar to the parent on the mouse colon in vivo. When given centrally, they all dose-dependently inhibited colonic bead expulsion and retarded the rate of large intestinal transit in mice in a naloxone-sensitive manner. They also induced dose-dependent contraction on the isolated longitudinal muscle strips of mouse distal colon, which were significantly antagonized by naloxone,β-funaltrexamine, tetrodotoxin and indomethacin. Differences among the synthetic tetrapeptides in both in vivo and in vitro studies suggested that N-terminal cationization had a greater influence on the regulation of the colonic motor actions relative to the C-terminal halogenation. We compared the inhibitory effects of morphine and these peptides on the electrical field stimulation (EFS)-induced cholinergic bronchoconstriction in normal rats. All of the drugs tested inhibited the EFS-induced cholinergic constriction in rat isolated bronchus in a concentration- and frequency-dependent and naloxone-sensitive manner. The inhibitory effect of EM-1 on the EFS-induced bronchoconstriction was stronger than that of the same dose of morphine as well as the five EM-1 derived peptides at the same frequency. Our results indicated that N-terminal cationization and C-terminal halogenation showed opposite influences on the inhibitory effects of the four D-Ala-containing peptides in rat isolated bronchus.
引文
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