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Details for Patent: 5,858,684

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Details for Patent: 5,858,684

Title: Method of screening calcium receptor-active molecules
Abstract:The present invention relates to the different roles inorganic ion receptors have in cellular and body processes. The present invention features: (1) molecules which can modulate one or more inorganic ion receptor activities, preferably the molecule can mimic or block an effect of an extracellular ion on a cell having an inorganic ion receptor, more preferably the extracellular ion is Ca.sup.2+ and the effect is on a cell having a calcium receptor; (2) inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (3) nucleic acids encoding inorganic ion receptor proteins and fragments thereof, preferably calcium receptor proteins and fragments thereof; (4) antibodies and fragments thereof, targeted to inorganic ion receptor proteins, preferably calcium receptor protein; and (5) uses of such molecules, proteins, nucleic acids and antibodies.
Inventor(s): Nemeth; Edward F. (Salt Lake City, UT), Brown; Edward M. (Milton, MA), Hebert; Steven C. (Wellesley, MA), Garrett, Jr.; James E. (Salt Lake City, UT), Van Wagenen; Bradford C. (Salt Lake City, UT), Balandrin; Manuel F. (Sandy, UT), Del Mar; Eric G. (Salt Lake City, UT)
Assignee: The Brigham and Women's Hospital, Inc. (Boston, MA) NPS Pharmaceuticals, Inc. (Salt Lake City, UT)
Filing Date:Jun 07, 1995
Application Number:08/480,751
Claims:1. A method of screening for a compound able to affect one or more activities of a calcium receptor comprising the steps of,

a) contacting a recombinant cell with a test compound, wherein said recombinant cell comprises a recombinant nucleic acid expressing said calcium receptor, provided that said cell does not have functional calcium receptor expression from endogenous nucleic acid, and

b) determining the ability of said test compound to affect one or more activities of said calcium receptor, and comparing said ability with the ability of said test compound to affect said one or more calcium receptor activities in a cell not comprising said recombinant nucleic acid;

wherein said recombinant nucleic acid comprises a calcium receptor nucleic acid selected from the group consisting of:

a) nucleic acid of SEQ ID NO 1,

b) nucleic acid of SEQ ID NO 2,

c) nucleic acid of SEQ ID NO 3,

d) nucleic acid of SEQ ID NO 4,

e) nucleic acid encoding the amino acid of SEQ ID NO 5,

f) nucleic acid encoding the amino acid of SEQ ID NO 6,

g) nucleic acid encoding the amino acid of SEQ ID NO 7,

h) nucleic acid encoding the amino acid of SEQ ID NO 8, and

i) a derivative thereof encoding said calcium receptor, wherein said derivative encodes a receptor having one or more activities of said calcium receptor and comprises at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to a complement of at least 20 contiguous nucleotides of the calcium receptor nucleic acid of any of (a), (b), (c), (d), (e), (f), (g), and (h).

2. The method of claim l, wherein said calcium receptor nucleic acid is SEQ ID NO 1.

3. The method of claim 1, wherein said calcium receptor nucleic acid is a SEQ ID No 1 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to a complement of at least 20 contiguous nucleotides of SEQ ID NO 1.

4. The method of claim 1, wherein said calcium receptor nucleic acid is SEQ ID NO 2.

5. The method of claim 1, wherein said calcium receptor nucleic acid is a SEQ ID NO 2 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides of SEQ ID NO 2.

6. The method of claim 1, wherein said calcium receptor nucleic acid is SEQ ID NO 3.

7. The method of claim 1, wherein said calcium receptor nucleic acid is a SEQ ID NO 3 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides of SEQ ID NO 3.

8. The method of claim 1, wherein said calcium receptor nucleic acid is SEQ ID NO 4.

9. The method of claim 1, wherein said calcium receptor nucleic acid is a SEQ ID NO 4 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides of SEQ ID NO 4.

10. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of SEQ ID NO 5.

11. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO 5 derivative comprising least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 5.

12. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of SEQ ID No 6.

13. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO 6 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 6.

14. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of SEQ ID NO 7.

15. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO 7 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridizations conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 7.

16. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of SEQ ID NO 8.

17. The method of claim 1, wherein said calcium receptor nucleic acid encodes the amino acid sequence of a SEQ ID NO 8 derivative comprising at least 20 contiguous nucleotides which can hybridize under stringent hybridization conditions to a complement of at least 20 contiguous nucleotides encoding the amino acid sequence of SEQ ID NO 8.

18. The method of any one of claims 3, 5, 7, 9, 11, 13, 15, or 17, wherein said derivative comprises at least 27 nucleotides which can hybridize under stringent hybridization conditions to the complement of at least 27 contiguous nucleotides of SEQ ID NO 1, 2, 3, or 4, or to the complement of at least 27 contiguous nucleotides encoding the amino acid sequence of SEQ ID NOs 5, 6, 7 or 8.

19. The method of claim 18, wherein said derivative comprises at least 45 contiguous nucleotides which can hybridize under stringent hybridization conditions to the complement of at least 45 contiguous nucleotides of SEQ ID NO 1, 2, 3, or 4, or to the complement of at least 45 contiguous nucleotides encoding the amino acid sequence of SEQ ID NOs 5, 6, 7 or 8.

20. The method of claim 1, wherein said test compound comprises an aromatic group.

21. The method of claim 20, wherein said aromatic group comprises a moiety selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, .alpha.- or .beta.-tetrahydronaphthy, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

22. The method of claim 21, wherein said aromatic group comprises a moiety selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

23. The method of claim 22, wherein said aromatic group comprises said phenyl moiety.

24. The method of claim 22, wherein said aromatic group comprises said 1- or 2- naphthyl moiety.

25. The method of any one of claims 1-17, wherein said recombinant nucleic acid is an expression vector.

26. The method of any one of claims 1-17, wherein said recombinant nucleic acid comprises an exogenous promoter transcriptionally coupled to said calcium receptor nucleic acid.

27. A method of identifying a calcimimetic compound, comprising the steps of:

a) contacting a cell comprising a calcium receptor with a test compound; and

b) determining the ability of said test compound to affect the ability of said calcium receptor to respond to extracellular Ca.sup.2+ in the presence and, in a separate experiment, in the absence of an activator of Protein Kinase C,

wherein said test compound comprises an aromatic group.

28. The method of claim 27, wherein said step b) involves the use of a Protein Kinase C activator selected from the group consisting of phorbol myristate acetate, mezerein and (-)-indolactam V.

29. The method of claim 27, wherein said method measures mobilization of intracellular Ca.sup.2+.

30. The method of any one of claims 27-29, wherein said aromatic group is selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, .alpha.- or .beta.-tetrahydronaphathyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy, and said test compound is not verapamil or D-600.

31. The method of claim 30, wherein said aromatic group comprises a moiety selected from the group consisting of; phenyl, 2-, 3-, or 4-pyridyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

32. The method of claim 31, wherein said aromatic group comprises said phenyl moiety.

33. The method of claim 31, wherein said aromatic group comprises said 1- or 2- naphthyl moiety.

34. The method of claim 27, further comprising the step of measuring the ability of said test compound to mimic one or more affects of extracellular Ca.sup.2+ at a second cell type comprising a calcium receptor.

35. A method of identifying a calcimimetic compound comprising the steps of:

a) contacting a cell comprising a calcium receptor with a test compound; and

b) determining the ability of said test compound to mimic the activity of extracellular Ca.sup.2+ at said calcium receptor under conditions where calcium influx is blocked,

wherein said test compound comprises an aromatic group.

36. The method of claim 35, wherein said method measures mobilization of intracellular Ca.sup.2+.

37. The method of any one of claims 35 or 36, wherein said aromatic group is selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, .alpha.- or .beta.-tetrahydronaphthyl, 1- or 2-naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy, and said test compound is not verapamil or D-600.

38. The method of claim 37, wherein said aromatic group comprises a moiety selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

39. The method of claim 38, wherein said aromatic group comprises said phenyl moiety.

40. The method of claim 38, wherein said aromatic group comprises said 1- or 2- naphthyl moiety.

41. A method of identifying a calcilytic compound comprising the steps of:

a) contacting a cell comprising a calcium receptor with a test compound; and

b) determining the ability of said test compound to inhibit calcium receptor activity at said calcium receptor,

wherein said test compound comprises an aromatic group.

42. The method of claim 41, wherein said method is carried out under conditions wherein influx of extracellular Ca.sup.2+ is inhibited.

43. The method of claim 42, wherein said method measures mobilization of intracellular Ca.sup.2+.

44. The method of any one of claims 41-43, wherein said aromatic group is selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, .alpha.- or .beta.-tetrahydronaphthyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy, and said test compound is not verapamil or D-600.

45. The method of claim 44, wherein said aromatic group comprises a moiety selected from the group consisting of: phenyl, 2-, 3-, or 4-pyridyl, 1- or 2- naphthyl, 1- or 2-quinolinyl, 2- or 3-indolyl, benzyl, and phenoxy.

46. The method of claim 45, wherein said aromatic group comprises said phenyl moiety.

47. The method of claim 45, wherein said aromatic group comprises said 1- or 2- naphthyl moiety.

48. The method of claim 39, further comprising the step of measuring the ability of said test compound to inhibit one or more effects of extracellular Ca.sup.2+ at a second cell type comprising a calcium receptor.
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