CN115677519A - L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用 - Google Patents
L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用 Download PDFInfo
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- CN115677519A CN115677519A CN202110833157.2A CN202110833157A CN115677519A CN 115677519 A CN115677519 A CN 115677519A CN 202110833157 A CN202110833157 A CN 202110833157A CN 115677519 A CN115677519 A CN 115677519A
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Abstract
本发明属于抗抑郁药研发领域，具体公开了L‑4‑溴‑犬尿氨酸及其在制备治疗抑郁症药物中的应用，申请人发现L‑4‑溴‑犬尿氨酸在抑郁症疾病小鼠模型中可有效改善抑郁组小鼠的抑郁症状，可有效增加抑郁组小鼠的重要抗抑郁指标去甲肾上腺素和5‑羟基色氨水平，恢复水平不逊于市售氟西汀（Fluoxetine），为治疗抑郁症药物的开发提供新的选择性和思路。
Description
技术领域
本发明属于抗抑郁药研发领域，具体涉及L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用。
背景技术
L-4-氯犬尿氨酸一种可以作为前体药物来治疗神经性疼痛的化合物药物。该药物的特点是不仅可以通过口服后快速被肠道吸收，并且能被大型神经氨基酸转运体通过主动运输穿越血脑屏障送达大脑神经部位，具有良好药学性质。其药效作用机制：大脑内的星形胶质细胞里的犬尿氨酸氨基转移酶(kynurenine aminotransferases，KATs)会将L-4-氯犬尿氨酸转化为7-氯犬尿喹啉酸，然后释放并作用于神经元GlyB位点来进行N-甲基-D-门冬氨酸受体的间接拮抗阻断，从而治疗由N-甲基-D-门冬氨酸受体过度兴奋。由于其是通过间接作用来调节神经兴奋而不具有传统抗抑郁药物成瘾性等副作用，吸引了一大批学者开展了相关的合成和功能研究。
通过对L-4-氯犬尿氨酸化学结构进行修饰和衍生化，是一种有效的发现和研发具有更好的药效活性的药物研发方法，但受限于化合物来源有限，目前L-4-氯犬尿氨酸的类似物还没有被进行相关抗抑郁功能的研究。这类化合物的结构特征是包含一个邻位氨基和酮结构的苯环基团，且苯环基团上的其他位点还可以进行不同取代基修饰来发现新的生物活性功能化合物。犬尿氨酸类化合物具有独特的结构和生理功能，具有重大的生物学意义。
本发明提供了一种新的犬尿氨酸类似物，是近年来首次用于治疗抑郁症模型的L-4-溴-犬尿氨酸的化合物。该类似物在抑郁症疾病小鼠模型中可有效改善抑郁组小鼠的抑郁症状，可有效增加抑郁组小鼠的重要抗抑郁指标去甲肾上腺素和5-羟基色氨水平，恢复水平不逊于市售氟西汀(Fluoxetine)，且好于L-4-溴-犬尿氨酸类似物L-4-氯-犬尿氨酸(美国FDA临床二期抗抑郁药物)，为治疗抑郁症药物的开发提供新的选择性和思路。
发明内容
本发明的目的在于提供了一种犬尿氨酸类似物，该类似物的化学式为C10H11N2O3Br，所述的类似物结构式为：
本发明的另一个目的在于提供了L-4-溴-犬尿氨酸在制备治疗抑郁症药物中的应用。为了达到上述目的，本发明采取以下技术措施：
一种犬尿氨酸类似物L-4-溴-犬尿氨酸，该类似物的化学式为C10H11BrN2O3，其结构式为：
本发明提供的L-4-溴-犬尿氨酸，可利用本利于常规的化学合成的方式进行，还可以使用生物合成的方法，包括下述步骤：
6-Br-吲哚、L-丝氨酸、磷酸吡哆醛、Pf0A9酶(SEQ ID NO.1所示蛋白)和Tar13酶(SEQ ID NO.2所示蛋白)，缓冲液混合进行反应，反应结束后，加入CF3COOH继续反应，离心，上清过滤即得。所述的缓冲液为以下两种缓冲溶液以体积比1：1混合：KPi缓冲液(50mMKH2PO4,pH＝8.0)和缓冲液(50mM Tris-HCl,20mM NaCl,10％甘油,pH＝8.0)。
L-4-溴-犬尿氨酸在制备治疗抑郁症药物中的应用，包括用于制备成增强去甲肾上腺素水平的药物或是增强5-羟基色氨水平的药物。
本发明的保护范围还包括：L-4-溴-犬尿氨酸用于制备抗抑郁症药物筛选模型。
与现有技术相比，本发明具有以下特点：
本发明首次提供了一种犬尿氨酸类似物L-4-溴-犬尿氨酸，可有效恢复重要抗抑郁指标去甲肾上腺素和5-羟基色氨水平，同时具有生物安全性，为抗抑郁药物的开发提供了新的选择性。
附图说明
图1为实施例2中给药后每周小鼠的体重变化结果示意图。
图2为药物治疗两周后小鼠1％蔗糖溶液消耗量的药物效果比较示意图。
图3为药物治疗两周后小鼠旷场实验的药物效果比较示意图。
图4为药物治疗两周后小鼠重要抗抑郁指标去甲肾上腺素和5-羟基色氨水平示意图。
具体实施方式
本发明所述技术方案，如未特别说明，均为本领域的常规方案；所述试剂或材料，如未特别说明，均来源于商业渠道。
实施例1：
一种犬尿氨酸类似物L-4-溴-犬尿氨酸(L-4-Br-kyruneniene)，该类似物的化学式为C10H11Br N2O3，其结构式为：
L-4-Br-犬尿氨酸的体外生物合成制备方法，包括：
反应步骤：在50mL生物合成反应体系中加入6-Br-吲哚(1mM)、L-丝氨酸(1mM)、磷酸吡哆醛(0.025mM)、Pf0A9酶(200U/mL，SEQ ID NO.1所示蛋白)和Tar13酶(300U/mL，SEQID NO.2所示蛋白)，其余为缓冲液，30℃反应36小时。反应结束后，加入2mLCF3COOH，30℃继续反应6h。待反应结束后，然后12000rpm离心10min，上清液过滤膜后用HPLC进行分析，得率为200mg/L。而分离出的L-4-Br-犬尿氨酸进行结构验证后氢谱数据与文献值一致。
所述的分离纯化使用的方法包括：C18反相高效液相色谱柱，水(A相，含有0.1％甲酸(v/v))和乙腈(B相)为流动相，流速为0.75mL/min；0-5min 5％B，5-15min 5-12％B，15-30min 12-15％B，30-35min 15-100％B，35-38min 100％B，38-40min 100-5％B，40-45min5％B。
所述的缓冲液为以下两种缓冲溶液以体积比1：1混合：KPi缓冲液(50mM KH2PO4,pH＝8.0)和缓冲液(50mM Tris-HCl,20mM NaCl,10％甘油,pH＝8.0)。
实施例2：
L-4-溴-犬尿氨酸在小鼠抑郁模型中对重要抗抑郁指标去甲肾上腺素和5-羟基色氨水平恢复提升：
1)建立小鼠抑郁模型
所用小鼠来自雄性C57BL/6小鼠(4-6周龄)，SPF级别，起始体重约10-15g。小鼠于无特定病原体(specific pathogen free,SPF)条件下饲养。饲养环境为22±2℃，相对湿度50％～60％，人工光照明暗各12h，给予充足的食物和饮水，每周固定时间更换垫料并交换笼子位置。适应性喂养7天后进行模型构建。
模型组：雄性C57BL/6小鼠接受21天长期慢性刺激。第1周，前3天游泳20min/天，后3d游泳40min/天；第2周:接受包括电击足底(电压40V，每次10s，间隔50s刺激1次，共30次)、冰水游泳(4℃,5min)、热应激(45℃,5min)、夹尾(止血钳，距尾根1cm，1min)等环境刺激；第3周：接受禁水、禁食、昼夜颠倒、明暗交替(1h照明，1h黑暗，进行12h)、拥挤等刺激组成的慢性中等不可预知应激刺激。
对照组(Normal)：对照组不经过上述模型构建的方案处理。小鼠于无特定病原体(spe cific pathogen free,SPF)条件下饲养。饲养环境为22±2℃，相对湿度50％～60％，人工光照明暗各12h，给予充足的食物和饮水，每周固定时间更换垫料并交换笼子位置。
2)模型效果验证：
除了对照组，其他各组小鼠经过上述模型构建的方案处理后，全部进行模型验证。所有动物进行眼眶取血，分离血清通过对小鼠血清去甲肾上腺素(NE)、5-羟色胺(5-HT)水平测定进行模型鉴定。
3)动物分组及给药
模型验证成功后，将动物分成以下几组(每组5只小鼠)：
a)对照组：未经过抑郁模型构建方案处理
b)模型组：进行模型构建，不进行药物处理；等量生理盐水灌胃，每天一次，连续14天；c)L-4-Cl-kynurenine(美国FDA临床二期抗抑郁药物)治疗组(低浓度)：按照25mg/kg的剂量腹腔注射，每天一次，连续14天；
d)L-4-Cl-kynurenine(美国FDA临床二期抗抑郁药物)治疗组(高浓度)：按照50mg/kg的剂量腹腔注射，每天一次，连续14天；
e)L-4-Br-kynurenine治疗组(低浓度)：按照25mg/kg的剂量腹腔注射，每天一次，连续14天；
f)L-4-Br-kynurenine治疗组(高浓度)：按照50mg/kg的剂量腹腔注射，每天一次，连续14天；
g)阳性药物市售氟西汀(Fluoxetine)组：生理盐水配制浓度为1mg/ml氟西汀溶液，给药剂量为10mg/kg的剂量腹腔注射，每天一次，连续14天。
4)观察及取材
每天记录动物的饮食、饮水情况；每周记录动物的体重变化。
图1中显示相比于对照组，L-4-Br-kynurenine治疗组在高浓度和低浓度的条件下，都未影响小鼠的体重明显下降，L-4-Br-kynurenine药物表现出生物兼容性和安全性。并且L-4-Br-kynurenine治疗组在低浓度下对抑郁模型小鼠的体重恢复到接近对照组水平，比市售售氟西汀组的体重恢复效果更为明显。
5)药物效果检测
5.1行为学实验
5.1.1蔗糖溶液消耗量
1％蔗糖溶液消耗量：测定前禁水、禁食24h，每周四晚18:00-19:00测定动物1h饮用1％蔗糖溶液的量。测定前后水瓶的重量差为动物1h饮用1％蔗糖溶液的量。1％蔗糖溶液消耗量以1h摄入1％蔗糖溶液的量(mg)/动物体重(g)进行评定。每周测定1次。
图2中显示L-4-Br-kynurenine治疗组在高浓度条件下对抑郁模型小鼠的蔗糖溶液消耗量恢复水平接近市售氟西汀组的体重恢复效果，且L-4-Br-kynurenine治疗组在高浓度和低浓度的条件下对对抑郁模型小鼠的蔗糖溶液消耗量恢复水平均于优于相同条件下L-4-溴-犬尿氨酸类似物L-4-Cl-kynurenine(美国FDA临床二期药物)治疗组效果。
5.1.2.旷场实验(给药后14天检测)
旷场实验在安静的环境中进行。将小鼠放入旷场箱内底面中心，同时进行摄像和计时。观察一定时间后停止摄像，观察时间为5min，通过摄像和计时软件计算每只小鼠在旷场中心、中心周边和旷场边缘停留时间所在比例。
图3结果显示，相对于其他药物治疗组，L-4-Br-kynurenine治疗组在低浓度条件下对小鼠旷场实验中的中心区域停留时间有更为明显的提升作用，显示出其对小鼠抗抑郁活动行为能力的改善。
5.2血清学检测(给药后14天检测)
血清检测指标包括：去甲肾上腺素(NE)、5-羟色胺(5-HT)采用荧光分光光度法和ELISA方法进行含量测定。
图4结果显示：相对于抑郁模型组，L-4-Br-kynurenine治疗组在高浓度条件下对抑郁模型小鼠的去甲肾上腺素(NE)和5-羟色胺(5-HT)能达到明显恢复提升，其对重要抗抑郁指标恢复提升水平接近市售氟西汀组的恢复效果。
5.3病理学检测：HE染色观察小鼠海马区神经元的损伤(给药后14天取样检测)
小鼠均于血清学检测实验后麻醉，用生理盐水灌注后取出动物脑组织，左侧分离出海马冻存，右侧脑部整个进行固定和石蜡包埋切片HE染色，观察小鼠海马区神经元的损伤。
结果显示抑郁模型组的小鼠海马区神经元相比于对照组小鼠有明显的损伤，L-4-Br-kynurenine治疗组在高浓度条件下对抑郁模型小鼠的海马区神经元损伤能达到明显恢复效果，其对抑郁模型小鼠的海马区神经元损伤修复水平接近市售氟西汀组的恢复效果。L-4-Br-kynurenine治疗组低浓度条件下，治疗效果与L-4-Cl-kynurenine相近。
从以上实验数据可知，新的类似物犬尿氨酸类似物L-4-溴-犬尿氨酸，可有效恢复重要抗抑郁指标去甲肾上腺素和5-羟基色氨水平，同时具有生物安全性。相较于L-4-氯-犬尿氨酸和市售氟西汀，L-4-溴-犬尿氨酸在小鼠行为学的恢复水平更为明显，为抗抑郁药物的开发提供了新的选择性。
序列表
<110> 立科时代（武汉）生物科技有限公司
<120> L-4-溴-犬尿氨酸及其在制备治疗抑郁症药物中的应用
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Claims (5)
1.一种犬尿氨酸类似物L-4-溴-犬尿氨酸，该类似物的化学式为C10H11BrN2O3，其结构式为：
2.权利要求1所述的L-4-溴-犬尿氨酸的制备方法，包括下述步骤：
6-Br-吲哚、L-丝氨酸、磷酸吡哆醛、SEQ ID NO.1所示的Pf0A9酶和SEQ ID NO.2所示的Tar13酶，缓冲液混合进行反应，反应结束后，加入CF3COOH继续反应，离心，上清过滤即得；所述的缓冲液为50 mM KH2PO4, pH = 8.0和50 mM Tris-HCl, 20 mM NaCl, 10% 甘油, pH= 8.0以体积比1：1混合。
3.权利要求1所述的L-4-溴-犬尿氨酸或利用权利要求2所述的制备方法制备的L-4-溴-犬尿氨酸在制备治疗抑郁症药物中的应用。
4.权利要求1所述的L-4-溴-犬尿氨酸或利用权利要求2所述的制备方法制备的L-4-溴-犬尿氨酸在制备增强去甲肾上腺素水平的药物或/和增强5-羟基色氨水平的药物中的应用。
5.权利要求1所述的L-4-溴-犬尿氨酸在制备抗抑郁症药物筛选模型中的应用。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5360814A (en) * | 1991-02-28 | 1994-11-01 | Merrell Dow Pharmaceuticals Inc. | NMDA antagonists |
| CN107949379A (zh) * | 2015-05-22 | 2018-04-20 | 维斯塔津治疗公司 | L‑4‑氯代犬尿氨酸的治疗用途 |
| US20180327351A1 (en) * | 2015-09-08 | 2018-11-15 | Cephalon, Inc. | Prodrugs of chlorokynurenines |
| US20180338956A1 (en) * | 2017-05-25 | 2018-11-29 | Glytech Llc | Combined therapy for nmdar antagonist-responsive neuropsychiatric disorders |
| CN113549661A (zh) * | 2020-04-26 | 2021-10-26 | 赤壁生合元科技有限公司 | 生物催化合成L-4-Cl-犬尿氨酸或L-4-Br-犬尿氨酸的方法及应用 |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5360814A (en) * | 1991-02-28 | 1994-11-01 | Merrell Dow Pharmaceuticals Inc. | NMDA antagonists |
| CN107949379A (zh) * | 2015-05-22 | 2018-04-20 | 维斯塔津治疗公司 | L‑4‑氯代犬尿氨酸的治疗用途 |
| US20180327351A1 (en) * | 2015-09-08 | 2018-11-15 | Cephalon, Inc. | Prodrugs of chlorokynurenines |
| US20180338956A1 (en) * | 2017-05-25 | 2018-11-29 | Glytech Llc | Combined therapy for nmdar antagonist-responsive neuropsychiatric disorders |
| CN113549661A (zh) * | 2020-04-26 | 2021-10-26 | 赤壁生合元科技有限公司 | 生物催化合成L-4-Cl-犬尿氨酸或L-4-Br-犬尿氨酸的方法及应用 |
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