Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Primate cell – per se
Patent
1996-05-14
1999-08-17
Hutzell, Paula K.
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Primate cell, per se
435325, 4352523, 4353201, 536 235, 530358, 530350, C12N 1512, C12N 1563, C12N 1585, C07K 14705
Patent
active
059393220
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
The present invention relates generally to a method of finding potentiators of receptors employing a screening procedure using the novel recombinant human steroid hormone receptor hereinafter called NER. The compound TOFA (5-(tetradecyloxy)-2-furan carboxylic acid) has been found through the above screening procedure employing NER to be a potentiator of ligands for other receptors, particularly G-protein coupled receptors, without having any independent effect on the receptors.
Compounds which activate the NER receptor, such as TOFA, potentiate the effects of nerve growth factor (NGF) and may be useful in the treatment of Alzheimer's disease. These compounds may also be useful in potentiating the effects of muscarinic agonists in the treatment of ocular hypertension. Further, compounds which activate the NER receptor are also useful in potentiating the effects of dopamine D1 antagonists in the treatment of psychoses, particularly schizophrenia, and in the treatment of movement disorders such as distonia, tardive dyskinesia and Gilles de la Tourette syndrome. Further NER activators may potentiate the prevention of the development of intraocular pressure induced by dopamine agonists in hydrodynamic disorders of the eye and in patients with increased intracranial pressure.
The novel recombinant steroid hormone receptor NER has been prepared by polymerase chain reaction techniques. Also disclosed are the complete sequence of human NER complementary DNA; expression systems, including a COS-stable expression system; and an assay using the COS expression system. In addition, the invention relates to a method for identifying functional ligands of the NER receptor.
BACKGROUND OF THE INVENTION
Retinoids, steroid and thyroid hormones and possibly other molecules produce their biological effects by binding to proteins of the steroid receptor superfamily. These receptors interact with specific DNA sequences and modulate gene expression (for reviews see J M Berg, Cell 57:1065-1068 (1989); R M Evans, Science 240:899-895 (1988); M Beato, Cell 56:335-344 (1989)). Sequence analysis and functional studies of these receptors revealed two important regions which exhibit a high degree of amino acid residue conservation. The highest level of similarity among the receptors is found in a region which contains nine cysteine residues that bind zinc atoms to form two "zinc fingers," which interact with the cognate steroid response elements of DNA (J Miller, et al., EMBO J 4:1609-1614 (1985); R M Evans, Cell 52:1-3 (1988)). The second region, which is less conserved, is the ligand-binding domain, responsible for the interaction with the hormone (J. Carlstedt-Duke, et al., Proc Natl Acad Sci USA 79:4260-4264 (1982). J. Carlstedt-Duke, et al., Proc Natl Acad Sci USA 84:4437-4440 (1987)). Recent studies have attributed additional functions to other domains of these receptors, such as protein-protein interaction that participates in transcriptional regulation (R Scule, et al., Cell 62:1217-1226 (1990); H F Yang, Cell 62:1205-1215 (1990); J M Holloway et al., Proc Natl Acad Sci USA 87:8160-8164 (1990)). The amino acid conservation in the DNA binding domain has led to the identification of new members of the steroid receptor superfamily.
For example, hER1 and hER2 have been cloned by low stringency hybridization of cDNA libraries with a DNA probe coding for the DNA binding domain of the estrogen receptor (Giguere, et al., Nature 331:91-94 (1988)). Similar approaches have led to the discovery of the retinoic acid receptors and the peroxisome proliferator activator receptor (PPAR) (I Issemann, et al., Nature 347:645-650 (1990); D J Mangelsdorf, et al., Nature 345:224-229 (1990)). Recently, three novel members of the Xenopus nuclear hormone receptor superfamily have been disclosed (C Dreyer, Cell 68:879-987 (1992)). In addition, U.S. Pat. No. 4,981,784 to Evans, et al. discloses the identification of a retinoic acid receptor and the use of chimeric constructs to produce hybrid receptors for the identification of no
REFERENCES:
patent: 4981784 (1991-01-01), Evans et al.
patent: 5030576 (1991-07-01), Dull et al.
Arbeeny, J. Lipid Res., vol. 3, pp. 843-851 (1992).
Shinar et al., Gene, vol. 147, No. 2, pp. 273-276 (1994).
Apfel et al., Molecular and Cellular Biol., vol. 14, pp. 7025-7035 (1994).
Song et al., Proceedings of the Nat'l Academy of Sci., USA, vol. 91, No. 3, pp. 10809-10813 (1994).
Seol et al., Molecular Endocrinol., vol. 9, No. 1, pp. 72-85 (1995).
Teboul et al., Proceedings of the Nat'l Academy of Sci., USA, vol. 92, No. 6, pp. 2096-2100 (1995).
Beato, M. Cell, vol. 56, pp. 335-344 (1989).
Isseman et al., Nature, vol. 347, pp. 645-650 (1990).
Mangelsdorf et al., Nature, vol. 345, pp. 224-229 (1990).
McGurk et al., Neuroscience, vol. 50, No. 1, pp. 129-135 (1992).
virno et al., Opthalmol., vol. 16, No. 4-5 pp. 349-353 (1992).
Boyson et al., Ann. Neurol., vol. 27, No. 6, pp. 631-635 (1990).
Lee et al., Drug News Perspec., vol. 6, No. 7, pp. 488-497 (1993).
Stryer et al., Ann. Rev. Cell. Biol., No. 2, pp. 391-419 (1986).
Chao et al., Science, vol. 232, pp. 518-521 (1986).
Levi-Montalcini et al., Sci. Amer., vol. 240, No. 6, pp. 68-77 (1979).
Gilman, Ann. Rev. Biochem., vol. 56, pp. 615-649 (1987).
Berg, J.M. Cell, vol. 57, pp. 1065-1068 (1989).
Evans, Science, vol. 240, pp. 899-895 (1988).
Olson, Acta Neurochirurgica, vol. 58, pp. 3-7 (1993).
Seiger et al., Behavioral Brain Research, vol. 57, pp. 255-261 (1993).
Shinar et al., Gene vol. 147, pp. 273-276 (1994).
Power et al., Science, vol. 254 (5038), pp. 1636-1639 (1991).
Power et al., Trends Pharmacol. Sci., vol. 13, No. 8, pp. 1636-1639 (1991).
Lomax et al., Proc. West Pharmacol. Soc., vol. 34, pp. 5-9 (1991).
Witkin et al., Psychopharmacol. Berl., vol. 104, No. 4, pp. 452-431 (1991).
Ribeneau-Gyon et al., FEBS LETT, vol. 62, pp. 309-312 (1976).
Halvorson et al., Lipids, vol. 19, No. 11, pp. 851-856 (1984).
Otto et al., Arch. Biochem. Biophys., vol. 242, No. 1, pp. 23-31 (1985).
Paarker et al., J. Med. Chem., vol. 20, pp. 781-791 (1977).
Davis et al., Mol. Endocrinol., vol. 5, No. 6, pp. 854-859 (1991).
Green et al. Nature 320 (1986) 134-139.
Rodan Gideon A.
Rutledge Su Jane
Schmidt Azriel
Vogel Robert L.
Coppola Joseph A.
Hayes Robert C.
Hutzell Paula K.
Merck & Co. , Inc.
Tribble Jack L.
LandOfFree
Human steroid receptor does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Human steroid receptor, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Human steroid receptor will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-314546