CN104147016B - 冷薄荷醇受体trpm8的低分子量调节剂的检测和用途 - Google Patents

冷薄荷醇受体trpm8的低分子量调节剂的检测和用途 Download PDF

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CN104147016B
CN104147016B CN201410336374.0A CN201410336374A CN104147016B CN 104147016 B CN104147016 B CN 104147016B CN 201410336374 A CN201410336374 A CN 201410336374A CN 104147016 B CN104147016 B CN 104147016B
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trpm8
compound
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conditioning agent
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CN104147016A (zh
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T·萨布科夫斯基
C·博尔施韦勒
J·维特恩伯格
M·克龙
H·青克
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BASF SE
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Abstract

本发明涉及冷薄荷醇受体TRPM8的低分子量调节剂的检测和用途。具体而言，本发明涉及冷薄荷醇受体TRPM8的新调节剂，使用这些调节剂调节TRPM8受体的方法；所述调节剂用于诱导冷感觉的用途；以及使用这些调节剂制备的物品和工具。

Description

冷薄荷醇受体TRPM8的低分子量调节剂的检测和用途
本申请为2009年8月26日提交的、发明名称为“冷薄荷醇受体TRPM8的低分子量调节剂的检测和用途”的PCT申请PCT/EP2009/061019的分案申请，所述PCT申请进入中国国家阶段的日期为2011年2月28日，申请号为200980133390.7。
技术领域
本发明涉及冷薄荷醇受体TRPM8的新型调节剂，使用这些调节剂调节TRPM8受体的方法；所述调节剂诱导冷感觉的用途；以及使用这些调节剂制备的物品和组合物。
背景技术
冷薄荷醇受体TRPM8(也称为冷膜受体(CMR)1)属于“瞬时受体电位离子通道”家族，在一类特定的神经元中表达，在细胞膜中形成空穴(在各种情况下4个单元结合形成四聚体)，其选择性的允许Ca2+离子通过。所述蛋白具有6个跨膜结构域以及胞质C和N末端。低温(优选10-25℃)能刺激该受体，产生信号转导，所述信号被神经***理解为冷感觉。该受体在2002年在多篇出版物中首次被描述为冷觉受体(Peier AM等，感觉冷刺激和薄荷醇的TRP通道，2002Mar8；108(5):705-15；McKemy DD等，冷受体的鉴定揭示了TRP通道在热感觉中的普遍作用，Nature.2002Mar7；416(6876):52-8；Zuker CS.神经生物学：冷离子通道，Nature.2002Mar7；416(6876):27-8)。
致冷的化合物，例如薄荷醇，很长时间以来在调味剂和芳香剂工业中具有重要作用，以产生新鲜和清洁感的结合。对于化合物薄荷醇来说，已显示其作为受体TRPM8的天然调节剂起作用(McKemy D.D.,Molecular Pain1,2005,16；McKemy D.D.,Nature416,2002,52-58；Peier A.M.,Cell108,2002,705-715；Dhaka A.,Annu.Rev.Neurosci.29,2006,135-161)。通过应用薄荷醇，激活TRPM8，使得Ca2+流入冷敏神经元中。产生的电信号最终被感知为冷感觉。薄荷醇浓度升高可导致刺激和麻醉效应。此外，许多出版物描述了具有类似效应的薄荷醇衍生物(英国专利1971#1315761；Watson H.R.,J.Soc.Cosmet.Chem.29,1978,185-200；Furrer S.M.,Chem.Percept.1,2008,119-126)。还有结构上与薄荷醇不相关的个别化合物也产生了显著的TRPM8调节效应，例如Icilin(Wei E.T.,J.Pharm.Pharmacol.35,1983,110-112；WO 2004/026840)、WS-23或专利申请WO 2007/019719中所列的化合物。
调节TRPM8受体和/或其昆虫中的类似物的物质的另一种效应是对昆虫的驱除作用(WO 2002/015692；WO 2004/000023、US 2004/0028714)，其在抗肿瘤治疗(例如影响***肿瘤)、炎性疼痛/痛觉过敏的治疗中也具有活性，并且可用作TRPM8拮抗剂来有效治疗膀胱综合征或膀胱活动过度(Beck B.Cell Calcium,41,2007,285-294；LevineJ.D.Biochim.Biophys.Acta,Mol.Basis Dis.1772,2007,989-1003；Mukerji G.,BMCUrology6,2006,6；US 2003/0207904；US 2005/6893626,Dissertation BehrendtH.J.2004, Bochum；Lashinger E.S.R.Am.J.Physiol.Renal Physiol.Am JPhysiol Renal Physiol.2008Jun18.[在出版之前的电子版]；PMID:18562636)。
然而，迄今为止许多TRPM8调节剂在效应强度、效应持续时间、皮肤/粘膜刺激、气味、味觉、溶解性和/或挥发性方面仍具有缺陷。
发明内容
因此，本发明的一个目的是鉴定调节TRPM8受体的新物质，其可用作迄今已知的调节剂的备选物。这些化合物还应当尤其适用于化妆品(例如护发、护肤、口腔护理)、营养品(饲料/食物)、纺织品、OTC产品(例如烧伤软膏)、药物(例如肿瘤治疗、膀胱虚弱)、包装领域或作为杀虫剂或驱虫剂。
发明详述:
1.通用术语定义：
在文献中，"TRPM8"有多个同义词：TRPP8、LTRPC6、CMR1、MGC2849、瞬时受体电位阳离子通道亚家族M成员8。在本发明的背景中，涵盖所有的名称。该受体的所有功能性修饰也包括在内，例如尤其是剪接变体，亚型，例如TRPM8CRA_a、TRPM8CRA_b，和来自各种生物体例如人、小鼠、大鼠中的所有类似受体。不同受体的核苷酸和氨基酸序列是本身已知的，在序列数据库中列出。因此，例如hTRPM8的序列信息可以登录号NM_024080表示。
在本发明的内容中，“调节剂”是指能在体内和/或体外作为TRPM8受体激动剂和/或拮抗剂起作用的化合物。
在本文中适当的调节剂可仅作为拮抗剂或激动剂起作用，或同时作为拮抗剂和激动剂起作用，此时，产生激动效应或拮抗效应取决于选择的具体调节剂的浓度。
在本文中，“激动剂”是指介导TRPM8受体活化，由此诱导Ca2+进入冷敏神经元，从而介导冷感觉的化合物。相反，“拮抗剂”是指阻碍TRPM8受体活化的化合物。
本发明的介导物可通过可逆或不可逆、特异性或非特异性结合TRPM8受体分子发挥其作用。通常，与受体分子的结合通过离子和/或非离子的例如疏水作用而非共价性的发生。在本文中，“特异性的”包括与一种或多种不同的TRPM8受体分子(例如不同来源或不同亚型的TRPM8分子)排他性的相互作用。相反，“非特异性的”是指所述调节剂与多种不同功能和/或序列的受体分子相互作用，但是可产生对TRPM8所希望的受体激动和/或拮抗调节(如上文所述)。
2.优选的实施方案
本发明首先涉及体外或体内调节冷薄荷醇受体TRMP8的方法，尤其是人TRPM8受体，其中所述受体与至少一种选自多环有机化合物的化合物接触，所述化合物在使用重组表达人TRPM8受体的细胞进行的细胞活性测试中、特别是在标准条件下调节了这些细胞对Ca2+离子的通透性。
在该部分中，“标准条件”理解为表示使用经人TRPM8转化的HEK293细胞进行的实验，该细胞加载了钙敏感染料(例如Fluo-4AM,即氟-4-乙酰氧基甲基酯)后加入测试化合物，并检测颜色变化，实验过程在37℃进行，如下文实施例3所述，或参见Behrendt等(2004)，见上文)。
特别的，所述调节化合物包含至少2个4-至7-元环，其各自独立地为碳环或杂环、单环或多环，其中在这些环中至少2个可任选稠合或螺连接。合适的环连接的其他非限制性实例包括环碳原子和/或环杂原子间的化学单键，通过2-6元碳桥连基团连接，其中各个碳原子可被诸如N、O或S的杂原子替换。此外，所述环和桥连基可任选携带取代基，所述取代基选自酮基、-OH、-SH、-CN、-NO2、-C1-6-烷基或C2-4-链烯基，其中在烷基或链烯基中，一个或多个H原子可被诸如F、Cl、Br或I的卤素替换。
在本文中碳环包含4、5、6或7个碳原子；除环碳原子外，杂环包括1-3个相同或不同的环杂原子，例如O、N和S原子。在本文中的环可以各自独立地是饱和的、单或多不饱和的，例如芳环。
本发明使用的调节剂对于细胞Ca2+通透性具有激动或拮抗效应。具体而言，所述调节剂是至少一种选自下表1中的式1-19的化合物。
表1：根据本发明的调节剂
其中化合物可以化学纯或富集形式存在，为单个立体异构体或立体异构体混合物形式。此外，所述化合物可以是不带电的或其盐形式，例如酸加成盐。官能团可任选被等价的化学基团替换；氟原子可被其他卤素原子，例如Cl、Br或I替换；氧原子(例如醚基)可被相应的硫基团替换，反之亦然；酮基团可被相应的亚硫酰基替换。上面具体描述的化合物是本身已知的化学物质，可商购或通过常规有机合成方法获得。
因此，例如下列化合物是已知的：
化合物1，CAS号:99602-94-5(3R-顺式)
化合物2，CAS号:165753-08-2
化合物3，CAS号:338771-57-6
化合物4，CAS号:878942-21-3
化合物5，CAS号:748783-13-3
如果修饰形式或衍生物也表现出需要的生物学活性(受体TRPM8的调节)，那么它们也是功能类似物或功能等价化合物。
此外，本发明还包括使具体公开的物质与固相载体偶联的衍生物；本领域技术人员已知可选择多种相应的接头/间隔基团。所述衍生化可在偶联至固相前进行，或仅仅由偶联产生。
本发明还涉及TRPM8受体调节剂、尤其是激动剂在诱导人和/或动物的冷感觉，尤其是局部的，即皮肤或口腔的冷感觉中的用途，其中所述调节剂如上文所定义。当化合物在上述细胞活性测试中表现出对于hTRPM8的激动效应时，称为“诱导冷感觉”。
本发明还涉及TRPM8受体调节剂作为药物组合物的活性成分的用途，其中所述调节剂如上文所定义。
本发明还涉及TRPM8受体调节剂在***癌治疗、膀胱虚弱治疗或疼痛治疗中的用途，其中所述调节剂如上文所定义。
本发明还涉及TRPM8受体调节剂作为昆虫驱虫剂或杀虫剂的用途，其中所述调节剂如上文所定义。
本发明还涉及TRPM8受体调节剂在诱导对以多种加工形式(例如纤维、织物、模塑)的包装(例如由纸或塑料制成)的冷感觉中的用途，其中特别是在接触包装材料时，冷感觉变得显著，其中所述调节剂如上文所定义。在该部分内容中，所述物质可通过多种途径与包装材料相结合：例如通过旋转涂层、凹印、微囊化形式、直接引入到包装材料中(例如挤压)、调节剂的适当衍生物的共价偶联(通过适当的间隔物/接头基团来帮助分子与包装材料可逆或不可逆地结合)。本领域技术人员已知合适的方法。
本发明还涉及TRPM8受体调节剂在诱导纺织品的冷感觉中的用途，其中所述调节剂如上文所定义。在该部分内容中，所述物质可通过多种途径与纺织品相结合：例如通过旋转涂层、凹印、微囊化形式、直接引入到纺织品材料中(例如挤压)、调节剂的适当衍生物的共价偶联(通过适当的间隔物/接头基团来帮助分子与纺织品材料可逆或不可逆地结合)。本领域技术人员已知合适的方法。
本发明还涉及根据上述定义的物质本身作为TRPM8受体调节剂的用途，尤其是作为激动剂和/或拮抗剂。
本发明还涉及包含至少一种上述定义的化合物的组合物。特别的，所述组合物选自：
a)药物组合物，例如抗肿瘤组合物，治疗膀胱疾病的组合物，止痛剂；
b)食物，例如冰激凌、奶油冻、乳油、饮料、糕饼。
c)口腔护理组合物，例如牙膏、漱口水、口香糖、口气清新剂。
d)护肤或护发组合物，例如防晒霜、晒斑膏、洗剂、洗发水、硬膏、漱口剂、洗液、剃毛霜、调节剂、洗面奶、肥皂、沐浴乳和沐浴泡沫、止汗剂、除臭剂。
e)驱虫剂、杀虫剂。
除了各种具体组合物的常规成分外，所述组合物包含有效量的至少一种本发明的调节剂。在该部分内容中，“有效”表示所述调节剂的浓度足以带来需要的效应，例如药理学效果或感觉效应，例如在应用所述组合物(例如应用至皮肤)后冷的嗅觉效应。
任选地，根据本发明的化合物可与其他已知的活性成分组合，尤其是那些具有相同效应的。例如，可与已知的制冷化合物组合，例如薄荷醇、薄荷酮、N-乙基-p-薄荷烷甲酰胺(WS-3)、N-2,3-三甲基-2-异丙基丁酰胺(WS-23)、乳酸薄荷酯( ML)、薄荷酮甘油缩醛( MGA)、琥珀酸单薄荷酯()、戊二酸单薄荷酯、O-薄荷基甘油、N,N-二甲基琥珀酸酰胺薄荷酯。
本发明还涉及纺织品，例如衬衫、长裤、袜子、毛巾，其采用至少一种上述定义的化合物整理(finish)(尤其在表面上)。
本发明还涉及与至少一种上述定义的化合物结合的包装材料。
现参照下述非限制性的工作实施例来描述本发明。
附图说明
图1显示了来自根据序列数据库登录号NM_024080的hTRPM8受体的(a)mRNA序列和(b)氨基酸序列。
图2显示了编码hTRPM8的质粒pInd_M8的载体图谱，其已用于转染HEK293细胞。
具体实施方式
实验部分:
实施例1–人TRPM8的克隆
人TRPM8受体克隆的起点是LnCaP cDNA文库。其例如可从商业获得(例如BioChain,Hayward,USA)或使用标准试剂盒从雄激素敏感的人***癌细胞系LnCaP(例如ATCC,CRL1740或ECACC,89110211)制备。
可使用标准方法PCR扩增和克隆编码TRPM8的序列(参见图1A；和http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi？db＝nuccore&id＝109689694)。通过这种方法分离的人TRPM8基因被用于制备质粒pInd_M8，其构建通过图2的质粒图谱进行说明。
或者，TRPM8基因也可通过合成制备。
实施例2-HEK293测试细胞的传代
制备稳定转染人TRPM8DNA(参见上述质粒pInd-M8)的HEK293细胞系作为测试细胞***。在本文中优选通过引入的质粒提供用四环素诱导TRPM8表达的HEK293。
本领域技术人员已知生产适当的测试细胞***的方法。例如，本发明使用的细胞的制备详情参见Behrendt H.J.等,Br.J.Pharmacol.141,2004,737-745或Behrendt的论文“Vergleichende funktionale Untersuchungen des Hitze-Capsaicin-Rezeptors(TRPV1)und des-Menthol-Rezeptors(TRPM8)in rekombinanten und nativenZellsystemen”.[热辣椒碱受体(TRPV1)和冷薄荷醇受体(TRPM8)在重组和天然细胞***中的功能比较研究],参见：
http://www-brs.ub.ruhr-uni-bochum.de/netahtml/HSS/Diss/BehrendtHansJoerg/diss.pdf。
特别引用这些文献公开的内容。
实施例3-TRPM8调节剂的测定
采用与已描述在文献中的试验相当的试验，参见Behrendt H.J.等人,Br.J.Pharmacol.141,2004,737-745。受体的激动或拮抗通过Ca2+敏感性染料(例如FURA,Fluo-4等)来量化。根据其自身特点，激动剂使Ca2+信号增加，拮抗剂例如在薄荷醇存在下使Ca2+信号减少(各自通过染料Fluo-4检测，其具有由Ca2+导致的不同的荧光性质)。
a)试验方法：
首先，在细胞培养瓶中以本身已知的方法制备转化的HEK细胞的新鲜培养液。使用胰蛋白酶从细胞培养瓶上分离测试细胞HEK293-TRPM8，按每100μl培养基40000细胞/孔接种在96孔板中(Greiner#655948聚-D-赖氨酸-涂覆)。为诱导受体TRPM8，向生长培养基中加入四环素(DMEM/HG,10％无四环素FCS,4mM L-谷氨酰胺,15μg/ml灭菌素,100μg/ml潮霉素B,1μg/ml四环素)。第二天，细胞加载Fluo-4AM染料，进行试验。使用下列步骤：
-在每100μl培养基(DMEM/HG,10％无四环素FCS,4mM L-谷氨酰胺,15μg/ml灭菌素,100μg/ml潮霉素B,1μg/ml四环素)中各自加入100μl/孔的染料溶液Ca-4kit(RB141,Molecular Devices)。
-在培养箱中孵育30分钟/37℃/5％CO2,30分钟/RT。
-制备供试物质(在200μl HBSS缓冲液中，不同浓度)和阳性对照(不同浓度的薄荷醇、icilin和离子霉素，在200μl HBSS缓冲液中)和阴性对照(仅200μl HBSS缓冲液)。
-以50μl/孔的量加入试验物质，在485nm激发、520nm发射测定荧光的变化(例如测定仪器FLIPR,Molecular Devices或NovoStar,BMG)，评价不同物质/浓度的效果，确定EC50值。
试验物质以浓度0.1-200μM一式三份进行测定。通常将化合物保存在DMSO溶液中，稀释至最大DMSO浓度2％进行测定。
b)试验结果
本发明调节剂测定的EC50值总结于下表2。
表2:试验物质对于人受体TRPM8的活性
该评价令人惊讶的发现，首次能够制备结构显著不同于已知的TRPM8受体激动剂，例如(-)薄荷醇、icilin和其他Behrendt H.J.等在Br.J.Pharmacol.141,2004,737-745(参见表1)中描述的激动剂的TRPM8受体激动剂，并且，在某些情况中其具有比(-)薄荷醇更好的活性，或与icilin效果相当。
实施例4–漱口剂的制备
制备下列组成的漱口剂：
乙醇95％ 177ml
山梨醇70％ 250g
根据表2的TRPM8激动剂，
F127，
为制备漱口剂，以所述量混合上述成分。
本文特别参考所引用的文献资源的公开内容。

Claims (16)

1.体外调节冷薄荷醇受体TRMP8的方法，其中所述受体与至少一种选自以下的化合物接触，所述化合物在使用重组表达人TRPM8受体的细胞进行的细胞活性测试中调节了这些细胞对Ca2+离子的通透性：
2.如权利要求1所述的方法，其中所述调节剂对于细胞Ca2+离子通透性具有激动或拮抗效应。
3.TRPM8受体调节剂在制备诱导人和/或动物的冷感觉的组合物中的用途，其中所述调节剂如权利要求1所定义。
4.TRPM8受体调节剂在制备用于***癌治疗、膀胱虚弱治疗或疼痛治疗的组合物中的用途，其中所述调节剂如权利要求1所定义。
5.TRPM8受体调节剂在制备作为昆虫驱虫剂或杀虫剂的组合物中的用途，其中所述调节剂如权利要求1所定义。
6.TRPM8受体调节剂在诱导包装的冷感觉中的用途，其中所述调节剂如权利要求1所定义。
7.TRPM8受体调节剂在诱导纺织品的冷感觉中的用途，其中所述调节剂如权利要求1所定义。
8.组合物，其包含至少一种选自如权利要求1所述的化合物2和3的化合物。
9.组合物，其包含至少一种如权利要求1所述的化合物，所述组合物选自：
a)药物组合物；
b)食物；
c)口腔护理组合物；
d)护肤或护发组合物；或
e)昆虫驱虫剂、杀虫剂。
10.如权利要求9所述的组合物，其为药物组合物，选自抗肿瘤组合物、膀胱疾病治疗组合物或止痛组合物。
11.如权利要求9所述的组合物，其为食物，选自冰激凌、奶油冻、乳油、饮料或糕饼。
12.如权利要求9所述的组合物，其为口腔护理组合物，选自牙膏、漱口水或口香糖。
13.如权利要求9所述的组合物，其为护肤或护发组合物，选自防晒霜、晒斑膏、洗剂、洗发水或硬膏。
14.纺织品，其采用至少一种如权利要求1所述的化合物整理。
15.如权利要求14所述的纺织品，其为衬衫、长裤、袜子或毛巾。
16.与至少一种如权利要求1所述的化合物结合的包装材料。
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