CN1471392A - 用于治疗神经性及神经心理性疾患的方法 - Google Patents
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Abstract
本发明公开了一种用于治疗动物(包括人)的心身性、抑郁性和神经精神性疾病的治疗方法，所述疾病例如为焦虑、抑郁、失眠、精神分裂、癫痫、痉挛和慢性疼痛。通过施用一种适当的吸诱素(attractin)抑制剂，可引起哺乳动物脑内的吸诱素酶或其异构体的活性下降，并由此导致神经肽Y(neuropeptide Y，NPY)及其类似底物的降解减少。该治疗可减少或减缓具有功能活性的神经元NPY(1－36)的浓度的下降，这导致内源性NPY(1－36)的稳定性增加，其结果是NPY的活性延长，由此导致NPY Y1受体活性功能性活化，从而从而有益于抗抑郁、抗焦虑、止痛、抗高血压以及其他的神经学作用。
Description
发明背景
发明领域
本发明涉及吸诱素(attractin)及其异构体在中枢神经系统(centralnervous system，CNS)内的功能，以及其对神经肽水平、神经传递和行为的生物学作用。本发明还涉及通过选择性抑制吸诱素及其异构体而加强脑内的神经肽Y(Neuropeptide Y，NPY)系统以及吸诱素的其他底物的内源性神经性和神经心理性作用。本发明进一步涉及通过抑制CNS内的吸诱素及其异构体而加强NPY Y1受体介导的效应从而对以下疾病进行治疗：高血压病、发热、睡眠障碍、厌食症、包括抑郁症在内的焦虑相关性疾病、包括癫痫在内的抽搐、药物戒断(drugwithdrawal)和酗酒、包括认知障碍和痴呆在内的神经退行性疾病、以及包括精神分裂症在内的神经精神性疾病。
技术背景NPY的发现过程
神经肽Y(NPY)是一种36个氨基酸的肽，属于胰多肽家族(pancreatic polypeptide family)，最初于1982年在猪脑中被分离出来(Tatemoto和Mutt，1982)。NPY存在于所有支配心血管系统的交感神经中，并且是脑和心脏中含量最丰富的肽。此外，在大鼠而非人类，NPY也存在于神经系统以外的血小板和内皮中(Zukovska-Grojec等，1993)。最初认为NPY是有效的血管收缩剂和神经调节剂。由于NPY在应激、运动、以及心肌缺血时释放，因此其被认为参与了冠心病、充血性心力衰竭、以及高血压的发病(Zukovska-Grojec等，1998)。由于近期发现NPY对食物摄取具有很强的刺激能力，因而猜测其在肥胖和糖尿病的发病中起了一定的作用(Kalra等，1999)。最近的研究提示NPY还是大鼠主动脉血管平滑肌细胞的一种有丝分裂原(Zukovska-Grojec等，1999)。
NPY相关性研究至少集中在三个主要方向：(1)共传递(co-transmission)和交感缩血管作用，这是由于其与去甲肾上腺素共表达；(2)CNS内的神经传递和功能，这是由于其强效的consummatory作用；以及(3)NPY的演化，这是由于NPY是已知的最为保守的生物活性肽之一(Colmers和Wahlestedt，1993：Lundberg，1996；Wahlestedt和Reis，1993；Wettstein等，1996)。NPY作用于至少6种受体(Y1-Y6)，具有不同的肽药理学并在CNS中具有截然不同的分布(Gehlert，1998)(表1)。NPY、NPY受体的亚型和mRNA的分布
NPY、NPY受体蛋白及其mRNA在人的CNS和大鼠脑内的分布最近已得到综述(Dumont Y，Jacques D，St-Pierre，J.-A，Tong，Y，Parker，R，Herzog H和Qurion，R，2000；化学神经解剖学手册，16卷：肽受体，部分I；Quirion，R，Bjorklund，A和Hkfeld，T，编者)。简要概括于表1。
含有NPY的神经元在包括人在内的多种动物的鼻粘膜有明显的分布，并通常与腺泡和血管相关联(Baraniuk等，1990；Grunditz等，1994)。对支配狗的鼻粘膜的副交感神经(翼管神经，vidian nerve)进行刺激可增加该区域的血流量，并主要引起阿托品抗性。静脉施用NPY可减少由于副交感神经刺激所引起的血管扩张，该作用不能被NPY Y1选择性激动剂[Leu31，Pro34]NPY所模拟，但可通过施用NPYY2受体激动剂N-乙酰[Leu28，Leu31]NPY(24-36)而模拟(Lacroix等，1994)。这与一种结合点前型(prejunctional)NPY Y2样受体所介导的对递质自副交感神经末端的释放的抑制作用相一致。NPY受体功能
NPY无疑是迄今为止所发现的最为丰富的神经肽，其在CNS和外周神经系统(PNS)具有广泛的分布。NPY与肽YY(PYY)(两者大约具有70％的同源性)和胰多肽(pancreatic polypeptide，PP)(两者大约具有50％的同源性)一同形成一种肽家族；NPY和PYY的生物活性尤其显著，而PP的活性通常弱的多(Gehlert，1998；Wahlestedt和Reis，1993)(表2)。
根据在体外分析系统中(Wahlestedt等，1986)与神经肽Y相比对一种截短的相关的肽YY-(13-36)的类似物的不同的反应性，将NPY的两种受体亚型称为神经肽Y Y1(结合点后型，postjunctional)和神经肽Y Y2(结合点前型，prejunctional)。神经元的结合点前型NPY受体的激活通常抑制神经活性，降低作为对神经冲动的应答和作为对促进神经递质释放的局部因子的应答的神经递质的释放(Wahlestedt等，1986)。所述结合点前型或神经肽Y Y2受体的分类是基于肽YY(13-36)的作用，但在多种系统中，该分子以及神经肽Y-(13-36)确实具有血管收缩活性(Rioux等，1986；Lundberg等，1988；Potter等，1989)。一些观点认为这代表一些血管床的结合点后膜具有两种类型的神经肽Y受体(神经肽YYj和神经肽Y2)(Schwartz等，1989)。而这些分子之所以缺乏选择性可能是因为其在Yj受体上保持了部分的激动剂活性，这使得它们引起了一种减弱了的功能性应答。以往曾描述了一种神经肽Y的13-36类似物(Leu 17，Glu＂，Ala21，Ala 22，Glu 23，LeU28，LeU31)，即神经肽Y-(13-36)(ANA神经肽Y-(13-36))，其在体内研究中具有相当于完整神经肽Y分子的结合点前活性(Potter等，1989)。
除却这些过去已经被详细说明的神经肽Y受体，药理学依据提示存在一些其他的亚型(Y3、Y4、Y5以及Y6)(Michel等，1998)，并且已经分别发表了克隆Y1、Y2、Y4和Y5受体的详细情况(Herzog等，1992；Gerald等，1995；Bard等，1995；Gerald等，1996)(表1)。这些不同的受体亚型的分布以及生理学意义还有待进一步确定。尽管对于神经肽Y的截短的形式对一种或另一种受体亚型的选择性一直存在争议(Potter等，1989)，但研究进展支持最初的结合点前和结合点后的受体亚型分类。已经建立了特异性表达一种神经肽Y受体亚型的细胞系，而具有受体选择性的神经肽Y类似物方面的进展主要集中于其在这些细胞系中的结合特征(Sheikh等，1989；Aakerlund等，1990；Fuhlendorff等，1990)。最近，一种编码神经肽Y Y1受体的cDNA已被克隆，而表达所述已被克隆的受体的细胞系已经被用于分析神经肽Y类似物的特异性结合(Herzog等，1992)以及由特异性类似物所引发的功能性应答。从这些有关结合性的研究中，并结合随后的体内研究，已有两种类似物被归类为可特异性作用于结合点后的神经肽Y Y1受体。这些具有神经肽YY受体选择性的类似物，(Pro34)神经肽Y和(Leu＂，Pro 34)神经肽Y，模拟了神经肽Y的升高血压的作用，并同样具有与仅表达神经肽Y Y受体的细胞系的结合，所述细胞系例如为表达克隆的神经肽Y Y受体的神经母细胞瘤细胞系SK-N-MC以及成纤维细胞系(Herzog等，1992)。两者均未显示出神经肽Y Y2受体作用即在体内抑制心脏迷走神经的作用，一种抑制乙酰胆碱释放的表现(Potter等，1991；Potter和McCloskey，1992)。
表1；NPY受体亚型在CNS内的分布和功能
| 受体亚型 | CNS表达 | 功能 | 选择性激动剂 | 选择性拮抗剂或选择性 |
| Y1 | 皮层，等 | 抗焦虑，LHRH释放 | 完整N端：[Leu31，Pro34]NPY | BIBP3226；BIBO 3304 |
| Y2 | 海马，下丘脑 | 抗遗忘 | C端末端：PYY3-36；PYY13-36 | T4[NPY(33-36)]4；BIIE0246 |
| Y3 | Ncl，TractusSolitarius(NTS) | 心动过缓，低血压 | NPY＞＞PYY，[Leu31，Pro34]NPY | PYY不敏感 |
| Y4 | 迷走神经背侧结(DVC) | 催吐 | PP＞＞NPY，PYY | PP优选 |
| Y5(a) | 下丘脑 | 喂食 | NPY，PYY，[Leu31，Pro34]NPY | [Leu31，Pro34]NPY敏感，BIBP3226不能逆转 |
| Y5(b)或Y6 | 下丘脑 | ？；种属特异性 | ？ | ？ |
| 表1：CNS内的NPY受体亚型；？＝未知或未研究 | ||||
具有高亲和性的、非肽类NPY拮抗剂BIBP3226和BIB03304的出现，十分有助于对NPY受体的功能性研究，这是由于该化合物对Y1R具有选择性，而至少对Y2R、Y3R和Y4R不具有活性(Doods等，1996)。近来报道了两种Y2受体拮抗剂。一种为TASP分子(Grouzmann等，1997)，另一种为非肽类拮抗剂(Wieland等，1999)，其他的非肽类的受体特异性化合物也已出现(Daniels等，1995)。因此，通过在脑内阻断特异性的受体，可以对由中枢性NPY受体介导的行为学和生理学效应进行功能性研究。此外，缺乏Y1R的小鼠也已经产生并可获得(Pedrazzini等，1998)。具有NPY样免疫反应性和NPY受体表达的神经元在CNS中含量丰富(表1)，且可能在下丘脑以及所谓的边缘结构(limbic structure)中最为明显，但其同样共定位于脑干单胺能性神经元(monoaminergic neuron)和皮质GABA能性神经元(GABA-ergic neuron)(Chronwall，1985；Dumont等，1996)。表2：受体亚型肽选择性
NPY，焦虑和抑郁
| 受体亚型 | 肽的效能 |
| Y1样Y1Y4Y6Y2样Y2Y5样Y5未克隆的PP受体Y3PYY优选 | NPY＝PYY＝Pro34-NPY＞PP＞NPY13-36PP＞＞NPY＝PYY＝LP-NPY＞NPY13-36NPY＝PYY＝Pro34-NPY＞NPY13-36＞PPNPY＝PYY＝NPY13-36＞Pro34-NPY＞PPNPY＝PYY＝Pro34-NPY＞NPY13-36＞PPPP＞＞PYY＝NPYNPY＝Pro34-NPY＝NPY13-36＞＞PYYPYY＞NPY＞＞NPY13-36＞＞Pro34-NPY |
| 表2：受体亚型肽选择性(根据1998年Gehlert)。 | |
NPY的抗焦虑样作用(anxiolytic-like effect)已通过使用elevatedplus maze test(Montgomery)、惩罚性饮水试验(punished drinking test，Vogel)、和惩罚性应答试验(punished responding test，Geller-Seifter)所证实，其效力和作用可与苯并二氮(benzodiazepine)相当(Griebel，1999；Heilig等，1989；Wettstein等，1995)。NPY在对新奇事物的应答(response to novelty)中发挥抗焦虑样作用(Heilig和Murison，1987；von B orsten等，1998b)，并在elevated plus maze和其他的焦虑相关性试验中产生抗焦虑样效应(Wahlstedt和Reis，1993；Wahlestedt等，1993)。有趣的是，经Y1受体的反义处理的大鼠(antisense-treated rat)表现出明显的焦虑相关性行为，但不出现运动和摄食的改变(Wahlestedt等，1993)。此外，在一种Flinder大鼠抑郁症模型上，Y1受体的mRNA表达在不同的皮质区域和海马齿状回(dentate gyrus of the hippocampus)是减低的，而Y2受体的mRNA表达与对照无区别(Caberlotto等，1998)。通过给大鼠进行嗅球切除术(Olfactory bulbectomy)建立了一种抑郁症模型(Leonard和Tuite，1981)。在该模型中出现的绝大多数的变化与抑郁症患者的症状相似(Song等，1996)。给切除嗅球的大鼠脑室内注射(i.c.v.)施用为期7天的NPY可减轻该动物模型的行为学和神经递质的缺陷(Song等，1996)。NPYY1、Y2、以及可能Y5受体似乎参与调节了啮齿动物的焦虑水平，其中Y1介导的效应被研究地最为深入(Heilig等，1993；Kask等，1998b)。因此可以认为，内源性NPY可对抗应激和焦虑(Heilig等，1994)。不仅如此，这些结果还提示Y1受体亚型可能参与了焦虑和抑郁相关性行为。此外，Kask等(1996)报道了脑室内注射Y1拮抗剂BIBP3226可在elevated plus-maze test中产生致焦虑样效应(anxiogenic-like effect)，但不出现任何运动异常。通过在背侧的导水管周边灰质(dorsal periaqueductal gray matter)施用BIBP3226也可产生此效应，但在篮斑(locus coeruleus)或视丘的脑室周边核施用却不能(Kask等，1998c)。此外，将BIBP3226和GR231118施用于背侧的导水管周边灰质，使大鼠的主动性社会交往减少(Kask等，1998d)。对于NPY发挥抗应激作用具有重要意义的脑部区域包括但不限于扁桃体(Sajdyk等，1999；Thorsell等，1999)，篮斑(Kask等，1998c)和背侧的导水管周边灰质(Kask等，1998a、b)。当用BIBP3226或BIB03304阻断NPY Y1R后，elevated plus-maze和社会交往试验并未发现焦虑加重，因此扁桃体NPY在低应激条件下并不释放(Kask等，1998b；Sajdyk，1999)。但是在背侧的导水管周边灰质似乎存在持续性NPY能性紧张度，在两个实验性焦虑模型中NPY Y1R拮抗剂均产生了致焦虑样效应(Kask等，1998a、b)。因此，在特定的脑部区域可能存在通过NPY系统对焦虑的紧张度调节。CNS NPY系统的神经学和精神生理学效应：多效性(pleiotropy)
因此，已有大量的研究致力于NPY及其同类物在CNS中的生理功能(见综述：Kalra和Crowley，1992；Dumont等，1992；Stanley，1993；Wahlestedt和Reis，1993；Grundemar等，1993；Gehlert，1994，1998；Colmers和Bleakman，1994；Wettstein等，1995；Heilig和Widerlow，1995；Munglani等，1996；Inui，1999；Bischoff和Michel，1999；Vezzani等，1999)并证明其具有广泛的效应。目前，尚未出现利用这些不同的生理功能的药理学方法。使用苯并二氮和NPY治疗焦虑相关性疾病在当前存在的问题
当前治疗焦虑的方法伴随若干问题：
被普遍用作抗焦虑药物的苯并二氮类属于低选择性或无选择性的非天然化合物。除了其抗焦虑活性，苯并二氮类还有镇静和抗癫痫的作用，并且还被认为可影响肌肉的放松。但是，其也伴有一些有害的不良反应，即疲劳、嗜睡、精力不集中、注意力和反应性下降。长期应用苯并二氮类会引起神经性疾病，例如共济失调、眩晕、腱反射丧失、肌肉和构音障碍。据推测使用苯并二氮类进行长期的治疗可致药物依赖和成瘾。
将直接脑室内注射施用神经肽Y作为焦虑症病人的长期治疗措施缺乏可行性。
发明内容
本发明的一个目的是提供一种有益于神经学和心理生理学效应的药物。本发明的一个特别的目的是提供一种吸诱素或吸诱素异构体的抑制剂以用于生产一种药物，所述药物可用于调节针对包括焦虑在内的应激而产生的行为和/或神经学适应性反应性。
此外，本发明的一个目的是通过提供一种药理学方法而克服或减少现有技术中存在的上述问题，并使哺乳动物脑内的NPY的活性和/或作用得以维持或延长。
这些目的是通过一种吸诱素或吸诱素异构体的抑制剂在生产一种用于调节针对包括焦虑在内的应激而产生的行为和/或神经学反应性的药物中的用途而解决的。
这导致由NPY Y1受体介导的内源性神经学或神经心理学效应增强，包括但不限于减轻焦虑、治疗被诊断为患有高血压、高血压病、发热、睡眠障碍、厌食症、包括抑郁症在内的焦虑相关性疾病、包括癫痫在内的抽搐、药物戒断和酗酒、包括认知障碍和痴呆在内的神经退行性疾病、以及包括精神分裂症在内的神经精神性疾病的对象。
图1所示为以DP IV和吸诱素(A)裂解处理RANTES 1-15和以吸诱素在无(左)和有(右)异亮氨酰噻唑烷半延胡索酸(isoleucyl-thiazolidine hemifumarate)(P32/98)存在的情况下裂解处理NPY的MALDI-TOF质谱图。
发明详述
与本领域中所提及的其他方法不同，本发明提供了一种低分子量的吸诱素或吸诱素异构体(同功酶)的抑制剂的口服治疗法。这一方便的发明代表了一种用于治疗哺乳动物的焦虑和其他神经学或心理学疾病的新途径。其使用方便，具有商业价值，并适合应用于治疗方案中，特别是对于人类疾病。
可口服的低分子量的吸诱素酶活性抑制剂例如为N-(N’-取代的氨基乙酰)-2-氰基吡咯烷，L-苏型-异亮氨酰噻唑烷，L-异-异亮氨酰噻唑烷(L-allo-isoleucyl thiazolidine)，L-苏型-异亮氨酰吡咯烷，L-异-异亮氨酰噻唑烷(L-allo-isoleucyl thiazolidine)，和L-异-异亮氨酰吡咯烷(L-allo isoleucyl pyrrolidine)。相关描述见US 6,001,155，WO99161431，WO 99/67278，WO 99/67279，DE 19834591，WO 97/40832，DE 19616486 C2，WO 98/19998，WO 00/07617，WO 99/38501，和WO 99/46272，其全文在此并入作为参考。
吸诱素是一种外肽酶(exopeptidase)，其选择性地在N端倒数第二的脯氨酸和丙氨酸残基后裂解肽链。目前已知有5种attactin的异构体。根据本发明，也可使用吸诱素样酶，对吸诱素样酶的选择可以通过例如下面的试验进行：对肽酶进行选择性在N端倒数第二的脯氨酸和丙氨酸残基后裂解肽的试验，选择出能够实现此裂解的肽酶并分离该肽酶。
吸诱素抑制剂的多种作用提示，当其被用于治疗发生病理变化的组织时，其会对正常健康组织和器官产生影响。本发明的目标是开发具有高选择性的、定向于脑的、吸诱素和吸诱素异构体抑制剂，其具有很高的生物利用度和靶组织内的可精确预测的活性时间。
可口服的低分子量药剂的例子为吸诱素酶活性的稳定和不稳定的抑制剂的前体药物(prodrug)，其包含通式A-B-C，其中A代表一种氨基酸，B代表A和C之间的化学键或者一种氨基酸，而C代表一种吸诱素酶活性的不稳定或稳定的抑制剂。见WO 99/67278，WO99/67279所述，其全文在此并入作方参考。
本发明涉及一种新型的治疗方法，其中由吸诱素酶的效应分子(effector)所引起的哺乳动物脑内的吸诱素酶或吸诱素异构体的活性的下降，由此而产生的结果是神经肽Y(NPY)的降解减少。该治疗可导致具有功能活性的NPY(1-36)的浓度的下降出现减少或延迟。
根据本发明可以看出，哺乳动物、特别是人的脑内的NPY的效应和/或活性可通过施用吸诱素或吸诱素异构体(同功酶)的抑制剂而得以维持或延长。由此可减少脑内NPY的降解。这可减轻或改善心身性、抑郁性和/或神经精神性疾病。这一方便的发明特别代表了一种治疗焦虑症以及其他神经学或心理学疾病的新型方法。其使用方便，具有商业价值，并适合应用于治疗方案中，特别是对于人类疾病。
令人惊异地，本发明人发现，施用吸诱素抑制剂异亮氨酰噻唑烷显示出抗焦虑效应。
吸诱素及其异构体存在并广泛分布于大鼠的脑中(Lu等，1999)。本发明人在实施例1中显示，NPY在体外是吸诱素的主要底物。
作为吸诱素活性被抑制而引起的内源性NPY(1-36)稳定性增加的结果，NPY的活性被延长，这导致具有功能活性的NPY Y1受体活性，而后者有益于抗抑郁、抗焦虑和抗高血压效应等(见上)。
本发明的用于治疗动物包括人的焦虑症的方法包含通过抑制吸诱素或吸诱素异构体而强化NPY的效应。在大多数情况下，吸诱素抑制剂可优选地通过口服施用。通过抑制吸诱素酶的活性，使活化形式的NPY的半衰期在生理条件下得以延长和维持。而延长存在的活化NPY可增强NPY Y1受体的活性。
本发明还提供了药物组合物，所述组合物包含一种治疗(或预防)有效量的所述抑制剂(和/或与吸诱素抑制剂一同施用的糖丸)，以及一种药用可接受的载体或赋形剂，其特别适合于定向于脑。合适的载体包括但不限于盐、缓冲盐、葡萄糖、水、甘油、乙醇、及其组合。所述载体和组合物优选地在良好的实验操作条件下进行，且最优选为无菌条件下。配方的选择在理论上要适合于施用方式，符合常规的操作。
适合的药用可接受的载体包括但不限于水、盐溶液(如NaCl)，酒精、阿拉伯树胶、植物油、苯甲醇(benzyl alcohols)、聚乙二醇、凝胶、碳水化合物例如乳糖、直链淀粉或淀粉、硬脂酸镁盐、滑石粉、粘性石蜡、芳香油、脂肪酸酯、羟甲基纤维素、和聚乙烯吡咯烷酮等。所述药用制剂可进行无菌处理，并在需要时混合入辅助剂，例如润滑剂、防腐剂、稳定剂、湿润剂、乳化剂、用于影响渗透压的盐、缓冲剂、着色剂、调味剂和/或芳香物质等等，其不应与所述活性化合物发生有害反应，但可改善其稳定性、可加工性和/或外观美感。
如果需要，所述组合物可以含有少量的湿润剂或乳化剂，或者pH缓冲剂。此外，所述组合物可以是液体溶液、悬浊液、乳液、片剂、丸剂、胶囊、控释剂型、或粉剂。此外，所述组合物可以通过传统的结合剂和载体如甘油三酯而配制成栓剂。口服配方可以包括标准的载体例如药用等级的甘露醇、乳糖、淀粉、硬脂酸镁盐、聚乙烯吡咯烷酮、糖精钠、纤维素、碳酸镁等。
进一步，所述组合物可根据常规程序配制为适合于给人静脉施用的药用组合物。有代表性地，静脉施用的组合物为无菌等渗缓冲溶液。必要时，所述组合物也可以包括溶剂以及局部麻醉剂，以减轻注射部位的疼痛。通常，所述成分可以单独形式提供或混合成单位剂型，例如密封容器内的冻干粉剂或无水浓缩物，所述容器例如为标明活性化合物量的安瓿或药囊(sachette)。若所述组合物以输液方式施用，其可以被置于含有无菌药用级水、盐或葡萄糖/水的输液瓶中。若所述组合物以注射方式施用，可提供一安瓿注射用水或盐水以便在施用前将所述成分进行混合。
最后，本发明的组合物可配制成中性或盐的形式。药用可接受的盐包括与游离氨基反应形成的盐，如衍生自盐酸、磷酸、乙酸、草酸、酒石酸等的盐，以及衍生自钠、钾、铵、钙、氢氧化铁、异丙胺、三乙胺、2-乙氨基乙醇、组胺、普鲁卡因等的盐。
用于治疗一种特定的疾病或病情的本发明的组合物的有效剂量取决于所述疾病或病情的性质，并可通过标准的临床技术加以确定。此外，可任选地通过体外和/或体内分析来确定最佳剂量的范围。配方中所用的确切剂量还将取决于施用途径、疾病的严重程度，并应根据医疗人员的判断和每个病人的具体情况而决定。
本领域人员应明白，对本发明在此给出的实施例和指导进行的各种改动，包括产生不同的吸诱素抑制剂和替代性治疗组合物，均未脱离本发明的精神和范围。
下面将结合实施例对本发明做进一步阐述，重点在于通过抑制吸诱素活性而产生的抗焦虑样和应激保护性样的作用。
实施例
实施例1
在体外，NPY是人吸诱素的一种底物
来自人血浆的吸诱素制备于取自健康人的100ml血浆(BaxterGmbH Germany，Plasmazentrum Halle)。使用惠普(Hewlett-Packard)G2025 LD-TOF系统来进行基质辅助的激光解离/离子化质谱(Matrix-assisted laser desorption/ionisation mass spectrometry)。
在有或无异亮氨酰噻唑烷(10μM)存在的情况下，用纯化的DP IV和吸诱素处理以获得肽(25μM)的质谱，为此，将底物与40mM tricine/HCI缓冲液(pH7.6)和酶溶液以2∶2∶1的比例在37℃温育。在不同的时间间隔将反应混合物的样品取出并与等量的基质溶液混合。通过将样品和基质进行混合分析，基质溶液的低pH值使得酶反应停止。将少量的此基质溶液转移至探针顶端并在惠普G2024A样品处理器(Hewlett-Packard G2024A Sample Prep Accessory)中立即蒸发。
吸诱素的蛋白裂解活性被进一步加以研究。经测定，Gly-Pro-pNA的Km值为0.14mM，与DP IV、吸诱素和一种血清DP IV样活性的值相当。此外还分析了诸如NP Y、RANTES、GIP、和胰高血糖素(Glucagon)等生物活性肽被纯化的吸诱素所裂解。类似于DP IV，吸诱素能够使NPY的N端的二肽Tyr-Pro释放(图1B，左)。当存在异亮氨酰噻唑烷时，裂解被抑制(图1B，右)。此前，曾报道了趋化因子(chemokine)RANTES被DP IV和吸诱素水解存在不同之处4。但是，我们的结果没有证实这些数据。与DP IV相似(图1A，左)，纯化的吸诱素能够自合成的RANTES1-15的N端相继释放第一个(Ser-Pro)和第二个(Tyr-Ser)二肽(图1A，右)。
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Claims (8)
1.吸诱素或吸诱素异构体的抑制剂在生产用于调节针对包括焦虑在内的应激的行为和/或神经学反应性的药物中的用途。
2.权利要求1的用途，其在于生产用于减少内源性的、定位于CNS的神经肽Y(NPY)以及其他具有类似特性的底物的降解的药物。
3.前述权利要求中任一项的用途，其在于生产用于治疗心身性、抑郁性和神经精神性疾病的药物。
4.权利要求3的用途，其特征在于所述心身性、抑郁性和神经精神性疾病选自焦虑症、抑郁症、失眠、慢性疲劳、精神分裂症、癫痫、进食障碍、痉挛和慢性疼痛。
5.前述权利要求中任一项的用途，其特征在于所述抑制剂与神经肽Y组合使用。
6.前述权利要求中任一项的用途，其特征在于所述抑制剂存在于一种具有生理学相容性的药物载体中。
7.前述权利要求中任一项的用途，其特征在于所述抑制剂被配制为所述抑制剂的前体药物。
8.前述权利要求中任一项的用途，其特征在于所述抑制剂通过肠道外、肠道内、口服、吸入或作为栓剂而使用。
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