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CN111803478B - 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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CN111803478B
CN111803478B CN202010795118.3A CN202010795118A CN111803478B CN 111803478 B CN111803478 B CN 111803478B CN 202010795118 A CN202010795118 A CN 202010795118A CN 111803478 B CN111803478 B CN 111803478B
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leu
val
modulator
composition
glu
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CN111803478A (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
本申请为中国发明申请201710396933.0的分案申请，该中国发明申请201710396933.0为中国发明专利申请201410336374.0的分案申请，所述中国发明专利申请201410336374.0是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，所述信号被神经系统理解为冷感觉。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，2002Mar 8；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.2002Mar 7；416(6876):52-8；Zuker CS.神经生物学：冷离子通道，Nature.2002Mar 7；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 Pain 1,2005,16；McKemy D.D.,Nature 416,2002,52-58；Peier A.M.,Cell 108,2002,705-715；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(例如影响前列腺肿瘤)、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.,BMCUrology 6,2006,6；US 2003/0207904；US 2005/6893626,Dissertation BehrendtH.J.2004,Bochum；Lashinger E.S.R.Am.J.Physiol.Renal Physiol.Am JPhysiol Renal Physiol.2008Jun 18.[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TRPM8 CRA_a、TRPM8 CRA_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受体调节剂在前列腺癌治疗、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前列腺癌细胞系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TRPM8 DNA(参见上述质粒pInd-M8)的HEK293细胞系作为测试细胞系统。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系统的方法。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)在重组和天然细胞系统中的功能比较研究],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40 000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(RB 141,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，
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。
序列表
<110> 巴斯夫欧洲公司
<120> 冷薄荷醇受体TRPM8的低分子量调节剂的检测和用途
<130> M/49197-PCT
<160> 2
<170> PatentIn 版本3.3
<210> 1
<211> 5621
<212> DNA
<213> 人
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aagaaaatcc tgcttgacaa aaaccgtcac ttaggaaaag atgtcctttc gggcagccag 60
gctcagcatg aggaacagaa ggaatgacac tctggacagc acccggaccc tgtactccag 120
cgcgtctcgg agcacagact tgtcttacag tgaaagcgac ttggtgaatt ttattcaagc 180
aaattttaag aaacgagaat gtgtcttctt taccaaagat tccaaggcca cggagaatgt 240
gtgcaagtgt ggctatgccc agagccagca catggaaggc acccagatca accaaagtga 300
gaaatggaac tacaagaaac acaccaagga atttcctacc gacgcctttg gggatattca 360
gtttgagaca ctggggaaga aagggaagta tatacgtctg tcctgcgaca cggacgcgga 420
aatcctttac gagctgctga cccagcactg gcacctgaaa acacccaacc tggtcatttc 480
tgtgaccggg ggcgccaaga acttcgccct gaagccgcgc atgcgcaaga tcttcagccg 540
gctcatctac atcgcgcagt ccaaaggtgc ttggattctc acgggaggca cccattatgg 600
cctgatgaag tacatcgggg aggtggtgag agataacacc atcagcagga gttcagagga 660
gaatattgtg gccattggca tagcagcttg gggcatggtc tccaaccggg acaccctcat 720
caggaattgc gatgctgagg gctatttttt agcccagtac cttatggatg acttcacaag 780
agatccactg tatatcctgg acaacaacca cacacatttg ctgctcgtgg acaatggctg 840
tcatggacat cccactgtcg aagcaaagct ccggaatcag ctagagaagt atatctctga 900
gcgcactatt caagattcca actatggtgg caagatcccc attgtgtgtt ttgcccaagg 960
aggtggaaaa gagactttga aagccatcaa tacctccatc aaaaataaaa ttccttgtgt 1020
ggtggtggaa ggctcgggcc agatcgctga tgtgatcgct agcctggtgg aggtggagga 1080
tgccctgaca tcttctgccg tcaaggagaa gctggtgcgc tttttacccc gcacggtgtc 1140
ccggctgcct gaggaggaga ctgagagttg gatcaaatgg ctcaaagaaa ttctcgaatg 1200
ttctcaccta ttaacagtta ttaaaatgga agaagctggg gatgaaattg tgagcaatgc 1260
catctcctac gctctataca aagccttcag caccagtgag caagacaagg ataactggaa 1320
tgggcagctg aagcttctgc tggagtggaa ccagctggac ttagccaatg atgagatttt 1380
caccaatgac cgccgatggg agtctgctga ccttcaagaa gtcatgttta cggctctcat 1440
aaaggacaga cccaagtttg tccgcctctt tctggagaat ggcttgaacc tacggaagtt 1500
tctcacccat gatgtcctca ctgaactctt ctccaaccac ttcagcacgc ttgtgtaccg 1560
gaatctgcag atcgccaaga attcctataa tgatgccctc ctcacgtttg tctggaaact 1620
ggttgcgaac ttccgaagag gcttccggaa ggaagacaga aatggccggg acgagatgga 1680
catagaactc cacgacgtgt ctcctattac tcggcacccc ctgcaagctc tcttcatctg 1740
ggccattctt cagaataaga aggaactctc caaagtcatt tgggagcaga ccaggggctg 1800
cactctggca gccctgggag ccagcaagct tctgaagact ctggccaaag tgaagaacga 1860
catcaatgct gctggggagt ccgaggagct ggctaatgag tacgagaccc gggctgttga 1920
gctgttcact gagtgttaca gcagcgatga agacttggca gaacagctgc tggtctattc 1980
ctgtgaagct tggggtggaa gcaactgtct ggagctggcg gtggaggcca cagaccagca 2040
tttcatcgcc cagcctgggg tccagaattt tctttctaag caatggtatg gagagatttc 2100
ccgagacacc aagaactgga agattatcct gtgtctgttt attataccct tggtgggctg 2160
tggctttgta tcatttagga agaaacctgt cgacaagcac aagaagctgc tttggtacta 2220
tgtggcgttc ttcacctccc ccttcgtggt cttctcctgg aatgtggtct tctacatcgc 2280
cttcctcctg ctgtttgcct acgtgctgct catggatttc cattcggtgc cacacccccc 2340
cgagctggtc ctgtactcgc tggtctttgt cctcttctgt gatgaagtga gacagtggta 2400
cgtaaatggg gtgaattatt ttactgacct gtggaatgtg atggacacgc tggggctttt 2460
ttacttcata gcaggaattg tatttcggct ccactcttct aataaaagct ctttgtattc 2520
tggacgagtc attttctgtc tggactacat tattttcact ctaagattga tccacatttt 2580
tactgtaagc agaaacttag gacccaagat tataatgctg cagaggatgc tgatcgatgt 2640
gttcttcttc ctgttcctct ttgcggtgtg gatggtggcc tttggcgtgg ccaggcaagg 2700
gatccttagg cagaatgagc agcgctggag gtggatattc cgttcggtca tctacgagcc 2760
ctacctggcc atgttcggcc aggtgcccag tgacgtggat ggtaccacgt atgactttgc 2820
ccactgcacc ttcactggga atgagtccaa gccactgtgt gtggagctgg atgagcacaa 2880
cctgccccgg ttccccgagt ggatcaccat ccccctggtg tgcatctaca tgttatccac 2940
caacatcctg ctggtcaacc tgctggtcgc catgtttggc tacacggtgg gcaccgtcca 3000
ggagaacaat gaccaggtct ggaagttcca gaggtacttc ctggtgcagg agtactgcag 3060
ccgcctcaat atccccttcc ccttcatcgt cttcgcttac ttctacatgg tggtgaagaa 3120
gtgcttcaag tgttgctgca aggagaaaaa catggagtct tctgtctgct gtttcaaaaa 3180
tgaagacaat gagactctgg catgggaggg tgtcatgaag gaaaactacc ttgtcaagat 3240
caacacaaaa gccaacgaca cctcagagga aatgaggcat cgatttagac aactggatac 3300
aaagcttaat gatctcaagg gtcttctgaa agagattgct aataaaatca aataaaactg 3360
tatgaactct aatggagaaa aatctaatta tagcaagatc atattaagga atgctgatga 3420
acaattttgc tatcgactac taaatgagag attttcagac ccctgggtac atggtggatg 3480
attttaaatc accctagtgt gctgagacct tgagaataaa gtgtgtgatt ggtttcatac 3540
ttgaagacgg atataaagga agaatatttc ctttatgtgt ttctccagaa tggtgcctgt 3600
ttctctctgt gtctcaatgc ctgggactgg aggttgatag tttaagtgtg ttcttaccgc 3660
ctcctttttc ctttaatctt atttttgatg aacacatata taggagaaca tctatcctat 3720
gaataagaac ctggtcatgc tttactcctg tattgttatt ttgttcattt ccaattgatt 3780
ctctactttt cccttttttg tattatgtga ctaattagtt ggcatattgt taaaagtctc 3840
tcaaattagg ccagattcta aaacatgctg cagcaagagg accccgctct cttcaggaaa 3900
agtgttttca tttctcagga tgcttcttac ctgtcagagg aggtgacaag gcagtctctt 3960
gctctcttgg actcaccagg ctcctattga aggaaccacc cccattccta aatatgtgaa 4020
aagtcgccca aaatgcaacc ttgaaaggca ctactgactt tgttcttatt ggatactcct 4080
cttattattt ttccattaaa aataatagct ggctattata gaaaatttag accatacaga 4140
gatgtagaaa gaacataaat tgtccccatt accttaaggt aatcactgct aacaatttct 4200
ggatggtttt tcaagtctat tttttttcta tgtatgtctc aattctcttt caaaatttta 4260
cagaatgtta tcatactaca tatatacttt ttatgtaagc tttttcactt agtattttat 4320
caaatatgtt tttattatat tcatagcctt cttaaacatt atatcaataa ttgcataata 4380
ggcaacctct agcgattacc ataattttgc tcattgaagg ctatctccag ttgatcattg 4440
ggatgagcat ctttgtgcat gaatcctatt gctgtatttg ggaaaatttt ccaaggttag 4500
attccaataa atatctattt attattaaat attaaaatat ctatttatta ttaaaaccat 4560
ttataaggct ttttcataaa tgtatagcaa ataggaatta ttaacttgag cataagatat 4620
gagatacatg aacctgaact attaaaataa aatattatat ttaaccctta gtttaagaag 4680
aagtcaatat gcttatttaa atattatgga tggtgggcag atcacttgag gtcaggagtt 4740
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tttagtgtag ttcacaataa tgtattgaac atacttctaa tcaaaggtgc tatgtccttg 5520
tgtatggtac taaatgtgtc ctgtgtactt ttgcacaact gagaatcctg cagcttggtt 5580
taatgagtgt gttcatgaaa taaataatgg aggaattgtc a 5621
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Claims (13)

1.体外调节冷薄荷醇受体TRMP8的方法，其中所述受体与以下的化合物接触，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对于细胞Ca2+离子通透性具有激动效应：
2.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，其中所述调节剂为权利要求1中所述的化合物。
3.TRPM8受体调节剂在制备用于膀胱虚弱治疗或疼痛治疗的组合物中的用途，其中所述调节剂为权利要求1中所述的化合物。
4.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，其中所述调节剂为权利要求1中所述的化合物。
5.TRPM8受体调节剂在诱导包装的冷感觉中的用途，其中所述调节剂为权利要求1中所述的化合物。
6.TRPM8受体调节剂在诱导纺织品的冷感觉中的用途，其中所述调节剂为权利要求1中所述的化合物。
7.包含如权利要求1中所述的化合物的组合物，其选自：
a)药物组合物；
b)口腔护理组合物；
c)护肤或护发组合物；
d)昆虫驱虫剂、杀虫剂。
8.如权利要求7所述的组合物，其为膀胱疾病治疗组合物或止痛组合物。
9.如权利要求7所述的组合物，其为牙膏、漱口水或口香糖。
10.如权利要求7所述的组合物，其为防晒霜、晒斑膏、洗剂、洗发水或硬膏。
11.纺织品，其采用至少一种如权利要求1中所述的化合物整理。
12.如权利要求11所述的纺织品，其为衬衫、长裤、袜子或毛巾。
13.与至少一种如权利要求1中所述的化合物结合的包装材料。
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