公开(公告)号：US20090069371A1

公开(公告)日：2009-03-12

申请号：US12274887

申请日：2008-11-20

申请人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Clare Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

发明人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Clare Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

IPC分类号： A61K31/47 ,  C07D217/22 ,  A61P27/02 ,  A61P9/00 ,  A61P1/00 ,  A61P15/08 ,  A61P35/00 ,  A61P19/08 ,  C12N5/00

CPC分类号： C07D217/02

摘要： Isoquinoline compounds with G are provided that influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.

摘要翻译： 提供了具有G的异喹啉化合物，其影响，抑制或降低G蛋白受体激酶的作用。 还提供包含治疗有效量的异喹啉化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症，骨质疏松症和青光眼的各种方法。

公开(公告)号：US20100093790A1

公开(公告)日：2010-04-15

申请号：US12639670

申请日：2009-12-16

申请人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Clare Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

发明人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Clare Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

IPC分类号： A61K31/472 ,  C07D217/02 ,  C07D401/12 ,  C12N5/00 ,  A61K31/4725 ,  A61P27/02 ,  A61P19/00 ,  A61P9/00 ,  A61P13/12

CPC分类号： C07D217/02

摘要： Isoquinoline compounds with G are provided that influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.

摘要翻译： 提供了具有G的异喹啉化合物，其影响，抑制或降低G蛋白受体激酶的作用。 还提供包含治疗有效量的异喹啉化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症，骨质疏松症和青光眼的各种方法。

公开(公告)号：US07470787B2

公开(公告)日：2008-12-30

申请号：US11485172

申请日：2006-07-11

申请人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Claire Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

发明人： Mitchell A. deLong ,  Marcos L. Sznaidman ,  Robert H. Oakley ,  Allen E. Eckhardt ,  Christine Hudson ,  Jeffrey D. Yingling ,  Michael Peel ,  Thomas E. Richardson ,  Claire Louise Murray ,  Byappanahally N. Narasinga Rao ,  Brian H. Heasley ,  Paresma R. Patel

IPC分类号： C07D217/00 ,  C07D401/00 ,  C07D215/00

CPC分类号： C07D217/02

摘要： Isoquinoline compounds with G are provided that influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.

摘要翻译： 提供了具有G的异喹啉化合物，其影响，抑制或降低G蛋白受体激酶的作用。 还提供包含治疗有效量的异喹啉化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症，骨质疏松症和青光眼的各种方法。

公开(公告)号：US07297503B2

公开(公告)日：2007-11-20

申请号：US10693164

申请日：2003-10-24

申请人： Carson R Loomis ,  Robert H. Oakley ,  Shuntai Wang ,  Allen E. Eckhardt

发明人： Carson R Loomis ,  Robert H. Oakley ,  Shuntai Wang ,  Allen E. Eckhardt

IPC分类号： G01N33/53 ,  G01N33/567 ,  G01N33/542 ,  C12Q1/66

CPC分类号： G01N33/566 ,  G01N2500/04

摘要： Described herein are methods of identifying a transmembrane receptor (TMR) agonist and compounds identified by this method. The TMR agonist (TMRA) is capable of activating TMR signaling while exhibiting reduced TMR internalization over a control compound.

摘要翻译： 本文描述了鉴定跨膜受体（TMR）激动剂和通过该方法鉴定的化合物的方法。 TMR激动剂（TMRA）能够激活TMR信号，同时在对照化合物上显示降低的TMR内化。

公开(公告)号：US07279324B2

公开(公告)日：2007-10-09

申请号：US10054616

申请日：2002-01-22

申请人： Larry S. Barak ,  Robert H. Oakley ,  Marc G. Caron ,  Stephane A. Laporte ,  Alyson Wilbanks

发明人： Larry S. Barak ,  Robert H. Oakley ,  Marc G. Caron ,  Stephane A. Laporte ,  Alyson Wilbanks

IPC分类号： C12N15/63 ,  C12N15/12

CPC分类号： A61K31/64 ,  A01K2217/05 ,  A61K31/41 ,  A61K38/00 ,  C07K14/705 ,  C07K14/723

摘要： The present invention relates to modified G-protein coupled receptors (GPCRs). The modified GPCRs of the present invention include GPCRs that have been modified to have altered DRY motifs such that the modified GPCRs are constitutively desensitized. As such, the modified GPCRs of the present invention preferably localize to endocytic vesicles or endosomes in an agonist-independent manner. The invention also relates to methods of screening compounds and sample solutions for GPCR activity using the modified GPCRs.

摘要翻译： 本发明涉及修饰的G蛋白偶联受体（GPCR）。 本发明的修饰的GPCR包括已被修饰为具有改变的DRY基序的GPCR，使得修饰的GPCRs被组成型脱敏。 因此，本发明的修饰的GPCR优选以不依赖于激动剂的方式定位于内吞囊泡或内体。 本发明还涉及使用修饰的GPCR筛选化合物和GPCR活性的样品溶液的方法。

公开(公告)号：US07455982B2

公开(公告)日：2008-11-25

申请号：US11084928

申请日：2005-03-21

申请人： Larry S. Barak ,  Robert H. Oakley

发明人： Larry S. Barak ,  Robert H. Oakley

IPC分类号： G01N33/53 ,  C12Q1/00 ,  C12N5/00 ,  C07K1/00

CPC分类号： C12N15/1089 ,  C12N2503/00 ,  G01N33/5076 ,  G01N33/566 ,  G01N2333/726 ,  G01N2500/04 ,  G01N2500/10

摘要： Methods of detecting G protein-coupled receptor (GPCR) activity in vitro and in vivo are provided. In one embodiment, the method includes providing at least one cell that expresses a GPCR and a plurality of conjugated proteins. Each of the plurality of conjugated proteins is formed by conjugating an arrestin protein and a detectable molecule. The plurality of conjugated proteins are substantially evenly distributed in the cytoplasm of the at least one cell. A first image of the at least one cell is obtained by detecting an amount of energy emitted from the detectable molecules and storing a value relative to the amount of energy. The at least one cell is treated with an agonist. A second image of the at least one cell is obtained. The first image and the second image are compared to detect the localization of at least some of the plurality of conjugated proteins at endocytic vesicles and/or endosomes.

摘要翻译： 提供了在体外和体内检测G蛋白偶联受体（GPCR）活性的方法。 在一个实施方案中，该方法包括提供至少一个表达GPCR和多个缀合蛋白的细胞。 通过将抑制蛋白和可检测分子结合来形成多个缀合的蛋白质中的每一个。 多个缀合的蛋白质基本上均匀地分布在至少一个细胞的细胞质中。 通过检测从可检测分子发射的能量的量并且存储相对于能量的值来获得至少一个细胞的第一图像。 用激动剂治疗至少一个细胞。 获得至少一个单元的第二图像。 比较第一图像和第二图像以检测多个缀合蛋白质中的至少一些在胞吞小泡和/或内体上的定位。

公开(公告)号：US07018812B2

公开(公告)日：2006-03-28

申请号：US09993844

申请日：2001-11-05

申请人： Robert H. Oakley ,  Lawrence S. Barak ,  Stephane A. Laporte ,  Marc G. Caron

发明人： Robert H. Oakley ,  Lawrence S. Barak ,  Stephane A. Laporte ,  Marc G. Caron

IPC分类号： C07K14/705 ,  C07K19/00 ,  C12N15/62

CPC分类号： C07K14/705

摘要： The present invention relates to modified G-protein coupled receptors (GPCRs). The modified GPCRs of the present invention include GPCRs that have been modified to have carboxyl terminal tails comprising one or more sites of phosphorylation, preferably one or more clusters of phosphorylation sites. The modified GPCRs of the present invention may comprise a retained portion of a carboxyl-terminus region from a first GPCR fused to a polypeptide, wherein the polypeptide comprises the one or more clusters of phosphorylation. The present invention also relates to methods of screening compounds and sample solutions for GPCR activity using the modified GPCRs.

公开(公告)号：US20090082410A1

公开(公告)日：2009-03-26

申请号：US11936939

申请日：2007-11-08

申请人： Robert H. Oakley ,  Christine C. Hudson

发明人： Robert H. Oakley ,  Christine C. Hudson

IPC分类号： A61K31/4164 ,  C12Q1/02 ,  G01N33/53 ,  C07K14/00 ,  A61P3/00 ,  A61P9/00 ,  C07H21/00 ,  C12N15/63 ,  C12N1/00

CPC分类号： H02M3/335

摘要： The present invention relates to agonist-independent methods of screening for compounds that alter GPCR desensitization. Included in the present invention are cell lines containing GRKs, in which GPCRs are desensitized in the absence of agonist; the GRKs may be modified. The present invention relates to methods to determine if a GPCR is expressed at the plasma membrane, and if the GPCR has an affinity for arrestin. Modified GPCRs which have increased arrestin affinity are included in the present invention. These modified GPCRs are useful in methods to screen for compounds that alter desensitization, including both the agonist-independent methods and agonist-dependent methods described herein.

摘要翻译： 本发明涉及用于筛选改变GPCR脱敏作用的化合物的与激动剂无关的方法。 本发明包括含有GRK的细胞系，其中GPCR在不存在激动剂的情况下脱敏; 可以修改GRK。 本发明涉及确定GPCR是否在质膜上表达的方法，如果GPCR对抑制素具有亲和力。 具有增加的抑制蛋白亲和力的修饰GPCR包括在本发明中。 这些修饰的GPCR可用于筛选改变脱敏的化合物的方法，包括本文所述的与激动剂无关的方法和激动剂依赖性方法。

公开(公告)号：US20090226949A1

公开(公告)日：2009-09-10

申请号：US12398027

申请日：2009-03-04

申请人： Lawrence S. Barak ,  Michael A. Shetzline ,  Robert H. Oakley ,  Marc G. Caron

发明人： Lawrence S. Barak ,  Michael A. Shetzline ,  Robert H. Oakley ,  Marc G. Caron

IPC分类号： C12Q1/46

CPC分类号： G01N33/5035 ,  G01N33/5008 ,  G01N33/5014 ,  G01N33/5091 ,  G01N33/74 ,  G01N2333/5758 ,  G01N2333/70571 ,  G01N2333/726

摘要： The present invention is related to the detection of GPCR ligands in a test sample by using a single cell biosensor expressing a GPCR. Preferably, the test sample is derived from a biological or environmental sample. This invention may be used to detect the presence of a disease or to detect the presence of a harmful agent in the environment. Included in the present invention is an array of biosensors that detect ligands of various GPCRs.

摘要翻译： 本发明涉及通过使用表达GPCR的单细胞生物传感器检测测试样品中的GPCR配体。 优选地，测试样品来自生物或环境样品。 本发明可用于检测疾病的存在或检测环境中有害物质的存在。 本发明包括检测各种GPCR的配体的生物传感器阵列。

公开(公告)号：US07332292B2

公开(公告)日：2008-02-19

申请号：US10788197

申请日：2004-02-26

申请人： Robert H. Oakley ,  Christine C. Hudson

发明人： Robert H. Oakley ,  Christine C. Hudson

IPC分类号： G01N33/566

CPC分类号： C07K14/705 ,  C07K14/723 ,  C07K2319/033 ,  C12N9/1205 ,  G01N33/573 ,  G01N2333/726 ,  G01N2500/10

摘要： The present invention relates to agonist-independent methods of screening for compounds that alter GPCR desensitization. Included in the present invention are cell lines containing GRKs, in which GPCRs are desensitized in the absence of agonist; the GRKs may be modified. The present invention relates to methods to determine if a GPCR is expressed at the plasma membrane, and if the GPCR has an affinity for arrestin. Modified GPCRs which have increased arrestin affinity are included in the present invention. These modified GPCRs are useful in methods to screen for compounds that alter desensitization, including both the agonist-independent methods and agonist-dependent methods described herein.

摘要翻译： 本发明涉及用于筛选改变GPCR脱敏作用的化合物的与激动剂无关的方法。 本发明包括含有GRK的细胞系，其中GPCR在不存在激动剂的情况下脱敏; 可以修改GRK。 本发明涉及确定GPCR是否在质膜上表达的方法，如果GPCR对抑制素具有亲和力。 具有增加的抑制蛋白亲和力的修饰GPCR包括在本发明中。 这些修饰的GPCR可用于筛选改变脱敏的化合物的方法，包括本文所述的与激动剂无关的方法和激动剂依赖性方法。