WO1994029447A2 - Dna coding for the human thyrotropin-releasing hormone receptor - Google Patents
Dna coding for the human thyrotropin-releasing hormone receptor Download PDFInfo
- Publication number
- WO1994029447A2 WO1994029447A2 PCT/GB1994/001250 GB9401250W WO9429447A2 WO 1994029447 A2 WO1994029447 A2 WO 1994029447A2 GB 9401250 W GB9401250 W GB 9401250W WO 9429447 A2 WO9429447 A2 WO 9429447A2
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- trh
- receptor
- gene
- probe
- trh receptor
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
- C07K14/723—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH receptor
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
Definitions
- This invention relates to the discovery of cDNA sequences encoding the human thyrotrophin-releasing hormone (TRH) receptor, and the application of this discovery to inter alia 1) the development and use of nucleotide sequences derived from the receptor for the measurement (qualitative and quantitative) and regulation of gene expression and 2) the development and use of TRH peptide agonist and antagonist analogues for clinical and therapeutic use in the management of human pituitary and thyroid dysfunction, cancers of the pituitary and thyroid and TRH related disorders of brain function .
- TRH thyrotrophin-releasing hormone
- TRH thyrotrophin
- PRL prolactin
- TRH-Test a specific provocative test of hormonal function
- TRH-Test This test is used to asses the status of TSH and prolactin secretion by the pituitary gland.
- TRH agonists have also been used in clinical trials.
- the analogue RX77368 has been used in controlled trials of patients with motor neurone disease, (Guiloff R.J. et al., 1986. J. Neurology, Neurosurgery and Psychiatry 49, 969-973), but with only limited success.
- TRH analogues are also believed to have potential therapeutic uses in Alzheimer's disease, (Metcalf G., 1982 Brain Res. Rev. 4, 389-408) and stroke, (Holaday J.W. et al., 1981 Science 213, 216-218), narcotic depression, psychiatric disorders, narcolepsy, hyperalgesia and colonic paralysis.
- TRH analogues are expected to be beneficial in reducing symptoms associated with neurological disorders such as motor neurone disease, spinocerebellar degeneration, (Sobue et al., 1980 Lancet i, 418-419) and brain and spinal injuries.
- TRH has been shown to be more effective than Naloxone an opiate receptor antagonist in improving cardiovascular function and survival in experimentally induced spinal injury in cats, (Faden A.I. et al., 1981 New Eng. J. Med. 305, 1063-1067).
- Other properties of TRH analogues may be useful in treating narcotic and anaesthetic overdose and opiate dependence, (Metcalf G., 1982 Brain Res. Rev. 4, 389-408). Accordingly there is a need for potent synthetic TRH analogues for such purposes also. Treatments with TRH itself or with known analogues are however inconvenient to administer, of limited efficacy, and/or difficult to control and adapt to individual requirements.
- TRH receptors in the brain and pituitary would be helpful both in attempting to use TRH or its analogs in behavioural pharmacotherapy without endocrine side effects and in attempting to understand the evolution of TRH's possible roles in the CNS.
- TRH receptors Species differences in the kinetics of the TRH receptor are known to exist, based on the binding of TRH analogues (Taylor St Burt 1982, J Neurochemistry 38,1649-1656) Furthermore sub-types exist of most receptors within a single species. This is in line with what is known for other transmembrane receptors where subtypes and alternatively spliced versions have been demonstrated.
- 412 amino acid sequence of the rat receptor is encoded by a DNA that contains 69 different nucleotides within the comparable coding regions plus 57 extra nucleotides at the COOH terminus (representing 90% overall homology) .
- 21 nucleotide changes result in 17 amino acid sequence changes.
- the significance of species differences has moreover been emphasized recently (Oksenberg et al., 1992 Nature 360: 161-163) where a single amino acid difference between human and rodent 5-HT 1B receptor proteins was found to result in major pharmacological differences.
- the present invention provides: a gene encoding human TRH receptor; and preferably a gene encoding human TRH receptor having the amino acid SEQ ID No:l disclosed herewith.
- the genes of the present invention may include nucleic acid sequences (upstream and/or downstream of the receptor coding sequence) which are utilized in the expression of the gene such as promoter, operator, and terminator sequences as well as other sequences which do not inhibit its expression.
- the expression "gene” includes DNA and/or RNA sequences as well as plasmid or viral "genes" containing the receptor gene and expression vectors for the gene.
- the present invention provides new methods and means based upon the newly discovered TRH-R polynucleotide sequence for use in the clinical diagnosis and therapeutic management of those processes and abnormalities thereof that involve the action of TRH and its receptor, including but not exclusive of:
- Thyroid Disease including Hyperthyroidism (any cause) , Subclinical hyperthyroidism; Diffuse nontoxic goiter (15%); Treated hyperthyroidism (6-12 months); Opthalmic Graves' disease (30%); Subclinical hypothyroidism;
- TRH-R cDNA sequences are also useful for the design of oligonucleotide probes capable of specifically hybridising with the genes of the present invention, and for the synthesis of polypeptides which may be used in immunoassays. Both oligonucleotide probes and the polypeptides may be useful for the diagnosis of TRH-R abnormalities.
- Polypeptides encoded within the cDNA sequences may also be used to raise antibodies against selected regions of normal or abnormal TRH-R polypeptide corresponding to one or more domains, or portions thereof of the TRH-R polypeptide, which are particularly implicated in ligand building i.e.
- the first, second, third and fourth extracellular domains of the TRH-R polypeptide see Figs.l and 2; or in signal transduction i.e. the first, second, third and fourth intra cellular domains, especially the main cytoplasmic loop or third intracellular domain, most preferably in the region of the interface between the third intracellular domain and the sixth transmembrane region. e.g. one of the four extra-cellular domains identified hereinbelow, and for the purification of antibodies directed against such regions.
- These antibodies may be useful in immunoassays for detecting normal or abnormal TRH-R in individuals.
- the present invention provides various means for detecting naturally occurring TRH-R polypeptides or genes i.e. both fully functional normal forms and abnormal forms which present one or more deinations whether this be in relation to altered ligand binding, or signal transduction, which may be found to occur within the human population.
- the invention provides screening means for use in the evaluation of new TRH agonists and antagonists, comprising a cell transformed with a recombinant expression system comprising an open reading frame (ORF) of DNA derived from a TRH-R genome or TRH-R cDNA, said ORF being operably linked to a control sequence compatible with said cell, as well as such expression systems per se.
- ORF open reading frame
- the present invention further includes a method of producing TRH receptor which method includes the step of expressing the genes of the present invention in a host, as well as TRH receptor produced by such a method.
- a method of producing TRH receptor which method includes the step of expressing the genes of the present invention in a host, as well as TRH receptor produced by such a method.
- eukaryotic hosts are generally preferred, e.g. Xenopus oocytes and COS-1 cells.
- Prokaryotic hosts that may be used include E. coli. and B. Subtilis. Fungi e.g. yeast may also be used.
- restriction enzyme analysis in this invention depends on Restriction Fragment Length Polymorphisms (RFLPs) .
- a sample is taken from any suitable tissue such as blood. DNA is extracted from the cells in any conventional way. It is then digested with an appropriate restriction enzyme e.g. one which cuts in CG- rich sequence. The fragments of different length are separated by gel electrophoresis in any conventional way. A restriction fragment pattern is generated. Probing of the fragments will generally be necessary for clearer detection of the pattern and of the fragment(s) of interest, e.g.
- n denotes any arbitrary number
- a polymorphism might generate restriction enzyme sites and thereby given rise to a plurality of shorter fragments where the normal DNA provides longer ones. Whether it is appropriate to probe for long or short fragments will therefore depend on the circumstances of the polymorphism. In some instances, the probe will extend outside the region designated.
- RFLP method is the currently preferred method of assay, it cannot be ruled out that direct hybridisation of probes to the TRH-R genomic region will be of interest.
- suitable biopsy or other samples can be subjected to cloning techniques, to isolate a library of genomic DNA. Clones containing the TRH-R gene can be amplified by
- PCR Polymerase Chain Reaction
- the cDNA of the invention also has uses in assays which are not of the RFLP type. Accordingly, the polynucleotides per se are part of this invention, as 'intermediates' suitable (when labelled) for use as probes. Both double-stranded and single- stranded polynucleotides are included as well as sense and anti-sense forms. Suitable polynucleotide probes will normally be a polynucleotide of from 10 to 50, preferably from 16 to 30 nucleotides in length. Shorter probes are unlikely to be sufficiently specific for the sequence of interest.
- probes of 100 nucleotides or more are likely to be inconveniently long, but up to 250 or more might be useful in some cases e.g. for chromosomal in- situ buybridisation as further described hereinbelow in the detailed examples.
- the probes relate to parts of the polynucleotide sequence corresponding to one or more domains, or portions thereof of the TRH-R polypeptide, which are particularly implicated in ligand building i.e. the first, second, third and fourth extracellular domains of the TRH-R polypeptide (see Figs. 1 and 2); or in signal transduction i.e.
- the probe will usually be of DNA and labelled in any suitable manner e.g. by labelling with an enzyme, radioisotope, fluorescent, luminescent, or chemiluminescent labels or biotinylation. It could also be of RNA.
- the fragments are probed under any appropriate conventional hybridisation conditions, the fragments being conveniently first transferred to a filter.
- the complexes thus formed are detected by autoradiography or other detection means appropriate to the particular kind of label used.
- the human cDNA cloned and sequenced is shown in Fig. 1.
- the nucleic acid and amino acid sequences shown in SEQ ID No. 1 herein are substantially identical to those disclosed in our earlier British Patent Application No. 9311854.5 from which priority has been claimed herein except for two nucleotides which had been misread but have now been corrected herein as follows: A at 728 now reads C resulting in Lys now reading as Thr in the polypeptide, and A at 897 now reads T resulting in Lys reading as Asn.
- Fig. 2 illustrates schematically the transmembrane, intracellular and extracellular domains of the receptor molecule.
- the transmembrane domains consist of seven stretches of hydrophobic in nature amino acids which span the membrane.
- the extracellular domain consists of four hydrophilic in nature amino acid stretches which exist exterior to the cells membrane. This region is believed to be important for the recognition of specific ligands.
- the intracellular domain consists of four hydrophilic stretches of amino acids which are thought to be involved in signal transduction.
- abnormality in human TRH-R and/or its expression may be "assayed" in a number of ways.
- the DNA encoding the TRH-R may itself be assayed for the presence or absence of abnormalities or the TRH-R polypeptide may be assayed for such purposes, where this is actually expressed.
- the former case generally involves the use of labelled polynucleotide probes to hybridise with DNA within the region coding for human TRHR polypeptide for the purposes of indicating the presence of absence of particular polynucleotide sequences.
- antibody probes are used to form antigen-antibody complexes with regions of the expressed TRH-R polypeptide for the purposes of indicating the presence or absence of particular polypeptide sequences.
- polynucleotide probes can be synthesized or otherwise produced with sequences corresponding to or complementary to the "abnormal" sequences, to allow screening of tissue samples for specific TRHR gene abnormalities.
- Suitable stretches of amino acids based on the cDNA sequence information provided by the present information may be synthesised on a peptide synthesiser. These peptides would generally have a length of from 10 to 50, preferably 15 to 30, amino acids but could be even shorter or longer.
- Polyclonal antibodies to these peptides may be produced by conventional approaches such as the immunisation of host animals (rabbit, goat etc.) with said peptides and recovery of the desired antibody material therefrom. Monoclonal antibodies could also be raised using conventional monoclonal antibody production procedures.
- say may be either qualitative or quantitative (e.g. where detection of under or over-expression of the receptor is required) .
- the PCR reaction product was sequenced, thereby providing provisional information covering approximately 300 nucleotides of the human receptor.
- a 26-mer oligonucleotide was synthesised on the basis of this human sequence and used as a probe to screen the human pituitary cDNA 5' stretch library. The probe was labelled with 3 2P by random hexamer priming.
- One positive clone was isolated from approximately lxlO 6 plaques.
- a secondary screen with the same human 26-mer oligonucleotide TRH-R cDNA probe isolated several positive clones. Purification of DNA from plate lysate stocks of six. putative TRH-R clones were performed according to a protocol described by Maniatis et al (1985) .
- DNA sequencing was carried out using an Applied Biosystems 373A automated DNA sequencer and Taq dye-deoxy terminator and primer sequencing protocols. Oligonucleotide primers for sequencing were produced on an Applied Biosystems 391 PCR-Mate DNA synthesiser. Analysis was carried out on Apple Macintosh computers and analysed using the sequence processor program GeneJockey (Biosoft, Cambridge, U.K.). Sequencing of this clone indicated the largest open reading frame as being 1086 bp. The ATG initiation codon was identified by comparison with both the rat and mouse TRH-Rs with which the human receptor shares high sequence homology.
- the nucleotide and deduced amino acid sequences for the human receptor are shown in Fig. 1.
- the human TRH- R was shown to encode a 398 amino acid protein (Fig. 2) , compared to 393 for the mouse TRH-R (Straub et al. 1992); and 412 (Zhao et al., 1992; de la Pefia et al., 1992); 411 (Sellar et al. , 1993) and 387 (de la Pena et al. , 1993) for the rat TRH-R.
- Our human clone contained only 130 bp of 3' untranslated region (UTR) and approximately 1 kb of 5'UTR (not sequenced) .
- the poly (A) tail was not present.
- the amplified 1.2 kb PCR product was purified through CHROMA SPIN TE-100 spin columns (Clontech) and subcloned into the EcoRl site of the pcDNA-1 vector (Invitrogen) in both orientations. The reverse orientation was used as a control during expression studies. The pcDNA-1 subclone was then sequenced again to ensure that no base changes had occurred as a result of mis-priming during the PCR amplification. Any base changes that resulted in amino acid changes could affect expression of the TRH-R protein in a human cell line. No such changes were discovered.
- Transfected COS-1 cells were washed twice with phosphate buffered saline and harvested by scraping. The cells were then suspended in assay buffer (20mM TRIS.HC1, 2mM MgCl 2 , pH7.4). Membranes were prepared following homogenisation and centrifugation (20,000xg, 30 min. , 4 C) . The membrane pellet was resuspended in assay buffer. Ligand binding assays were carried out with 3 H- labelled [3-Me-His 2 ]TRH in assay buffer at a final volume of 0.5ml. Following incubation on ice for 60 min., the membranes were filtered through Whatman GF-C filters and washed 3 times with assay buffer.
- the human TRH-R was subcloned (in both orientations) into a eukaryotic expression vector driven by the CMV promotor. Binding studies on membranes prepared from COS-l cells transiently transfected with the human TRH-R subclone showed the existence of a single high affinity binding site with a K d of 6.2 nM (Fig. 4). COS-l cells expressing the TRH-R in the correct orientation were exposed to TRH (10 " *M) . Total IP production increased approximately twofold. In either untransfected cells, or cells containing the receptor in the incorrect orientation (data not shown) , TRH was without effect. Results
- Figure 1 shows the gene encoding the human TRH receptor.
- the polynucleotide sequences specifically elucidated thus far are indicated along with the deduced amino-acid sequence;
- Figure 2 shows schematically the 7 transmembrane domains of the human TRH receptor and the 4 extracellular and 4 intracellular domains; and Figure 3 highlights amino acid differences at the COOH terminal tails of the TRH receptor in mouse, rat and human.
- metaphase chromosome spreads were obtained from two human males of normal karyotype. Chromosome spreads in marked slide areas were banded, photographed and destained prior to hybridization as previously described (Garson et al., 1987; Boyd et al., 1989) .
- Preparation of Labelled Polynucleotide Probes Two human TRH-R cDNA probes were prepared and used. The first clone consists of a 2.3 kb insert in XgtlO vector and includes the entire 1.2 kb coding region of the gene, 132 bp of 3' untranslated region and approximately 1 kb of 5' untranslated region.
- the second clone consists of the TRH receptor coding region, 18 bp of 5' untranslated region and 43 bp of 3' untranslated region inserted into the TA cloning vector pCRII (Duthie et al., 1993).
- the probes were labelled by nick translation with biotin-11-dUTP (Sigma) .
- the labelled probes were used at a concentration of 10-30 ng/ul for fluorescence in-situ hybridization according to the procedure described by Pinkel et al. (1986) . Modifications detailed by Carter et al. (1992) were employed but the pre-hybridization step was omitted for this single copy sequence probe.
- Hybridization was detected by incubation with avidin-fluroescein isothiocyanate (avidin-FITC, Vector Laboratories) and the signal amplified twice by two further incubations with biotinylated anti-avidin (Vector Laboratories) followed by avidin-FITC.
- Chromosomes were counterstained by mounting the slides in antifade AFl (Citifluor) containing 0.8 ug/ml 4,6-diaminidino-2-phenylindole (DAPI) and 0.4 ug/ml propidium iodide and examined using a Zeiss Axioplan fluorescence microscope. FITC and propidium iodide were excited at 490 nm (Zeiss filter combination 9) . Hybridization signals appear as yellow-green spots against the red propidium iodine counterstain. Previously photographed, DAPI-stained cells were relocated using Zeiss filter combination 1. Signals visualised on the post- hybridization metaphases using filter set 9 were marked on the photographs of pre-hybridization banded metaphases. The disribution of hybridization in chromosome spreads was analysed using the chi-square test. Results
- Duthie SM Taylor PL
- Anderson L Cook J
- Eidne KA Eidne KA
Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU70025/94A AU7002594A (en) | 1993-06-09 | 1994-06-08 | Dna coding for the human thyrotropin-releasing hormone receptor |
JP7501490A JPH09501310A (en) | 1993-06-09 | 1994-06-09 | DNA encoding the human thyroid stimulating hormone releasing receptor |
EP94918925A EP0701610A1 (en) | 1993-06-09 | 1994-06-09 | Dna coding for the human thyrotropin-releasing hormone receptor |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9311854.5 | 1993-06-09 | ||
GB939311854A GB9311854D0 (en) | 1993-06-09 | 1993-06-09 | Trh receptor action |
Publications (2)
Publication Number | Publication Date |
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WO1994029447A2 true WO1994029447A2 (en) | 1994-12-22 |
WO1994029447A3 WO1994029447A3 (en) | 1995-02-02 |
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ID=10736852
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1994/001250 WO1994029447A2 (en) | 1993-06-09 | 1994-06-09 | Dna coding for the human thyrotropin-releasing hormone receptor |
Country Status (5)
Country | Link |
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EP (1) | EP0701610A1 (en) |
JP (1) | JPH09501310A (en) |
AU (1) | AU7002594A (en) |
GB (1) | GB9311854D0 (en) |
WO (1) | WO1994029447A2 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0845045A1 (en) * | 1995-08-14 | 1998-06-03 | Cornell Research Foundation, Inc. | Regulation of cellular functions by ectopic expression of non-endogenous cell signalling receptors |
WO1998024818A1 (en) * | 1996-12-02 | 1998-06-11 | Astra Pharma Inc. | Novel trh receptor |
US5879896A (en) * | 1993-08-10 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Method of screening for inhibitors of human thyrotropin releasing hormone (TRH) receptor |
EP0950711A2 (en) * | 1998-02-06 | 1999-10-20 | Akzo Nobel N.V. | Gonadotropin receptor |
WO1999055732A1 (en) * | 1998-04-24 | 1999-11-04 | Astrazeneca Ab | A novel g-protein coupled receptor |
WO2001096562A1 (en) * | 2000-06-13 | 2001-12-20 | Merck Patent Gmbh | Thyrotropin-releasing hormone receptor-like gpcr (gprfwki) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IE20120542A1 (en) * | 2012-12-19 | 2014-07-02 | Provost Fellows Foundation Scholars And Other Members Of Board Of The College Of The Holy And Undivi | Novel TRH binding site in human CNS |
-
1993
- 1993-06-09 GB GB939311854A patent/GB9311854D0/en active Pending
-
1994
- 1994-06-08 AU AU70025/94A patent/AU7002594A/en not_active Abandoned
- 1994-06-09 JP JP7501490A patent/JPH09501310A/en active Pending
- 1994-06-09 WO PCT/GB1994/001250 patent/WO1994029447A2/en not_active Application Discontinuation
- 1994-06-09 EP EP94918925A patent/EP0701610A1/en not_active Withdrawn
Non-Patent Citations (4)
Title |
---|
BIOCHEM. BIOPHYS. RES. COMMUN., vol.195, 1993 pages 179 - 185 V. MATRE ET AL.; 'Molecular cloning of a functional human thyrotropin-releasing hormone receptor' * |
J. MOL. ENDOCRINOL., vol.10, 1993 pages 199 - 206 R.E. SELLAR ET AL.; 'Functional expression and molecular characterization of the thyrotrophin-releasing hormone receptor from the rat anterior pituitary gland' cited in the application * |
NEUROLOGY, vol.36, 1986 pages 641 - 644 S. MANAKER ET AL.; 'Autoradiographic localization of thyrotropin releasing hormone receptors in human brain' * |
PROC. NATL. ACAD. SCI. USA, vol.87, 1990 pages 9514 - 9518 R.E. STRAUB ET AL.; 'Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor' cited in the application * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5879896A (en) * | 1993-08-10 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Method of screening for inhibitors of human thyrotropin releasing hormone (TRH) receptor |
EP0845045A1 (en) * | 1995-08-14 | 1998-06-03 | Cornell Research Foundation, Inc. | Regulation of cellular functions by ectopic expression of non-endogenous cell signalling receptors |
EP0845045A4 (en) * | 1995-08-14 | 1999-11-24 | Cornell Res Foundation Inc | Regulation of cellular functions by ectopic expression of non-endogenous cell signalling receptors |
WO1998024818A1 (en) * | 1996-12-02 | 1998-06-11 | Astra Pharma Inc. | Novel trh receptor |
US6441133B1 (en) | 1996-12-02 | 2002-08-27 | Astrazeneca Canada Inc. | Thyrotropin-releasing hormone receptor 2(TRHR-2) |
EP0950711A2 (en) * | 1998-02-06 | 1999-10-20 | Akzo Nobel N.V. | Gonadotropin receptor |
EP0950711A3 (en) * | 1998-02-06 | 2003-09-17 | Akzo Nobel N.V. | Gonadotropin receptor |
WO1999055732A1 (en) * | 1998-04-24 | 1999-11-04 | Astrazeneca Ab | A novel g-protein coupled receptor |
US6800749B1 (en) | 1998-04-24 | 2004-10-05 | Astrazeneca Canada Inc. | G-protein coupled receptor |
US7238780B2 (en) | 1998-04-24 | 2007-07-03 | Astrazeneca Canada Inc. | G-protein coupled receptor |
WO2001096562A1 (en) * | 2000-06-13 | 2001-12-20 | Merck Patent Gmbh | Thyrotropin-releasing hormone receptor-like gpcr (gprfwki) |
Also Published As
Publication number | Publication date |
---|---|
GB9311854D0 (en) | 1993-07-28 |
WO1994029447A3 (en) | 1995-02-02 |
AU7002594A (en) | 1995-01-03 |
EP0701610A1 (en) | 1996-03-20 |
JPH09501310A (en) | 1997-02-10 |
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