Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-11-30
2003-12-02
Rotman, Al (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S454000, C549S220000, C552S107000, C552S113000
Reexamination Certificate
active
06656927
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a ligand of inositol-1,4,5-trisphosphate receptor.
BACKGROUND ART
D-Myo-inositol-1,4,5-trisphosphate (herein occasionally abbreviated as “IP
3
”) is a second messenger that binds to the IP
3
receptor to cause release of Ca
2+
from the Ca
2+
storage sites in cells, and it controls kinetics of intracellular Ca
2+
concentration in variety of cells. IP
3
plays an important role for control of various cellular functions such as secretion, insemination, muscular contraction, nervous signal transmission and cellular growth (Berridge, M. J., Nature, 361, 315, 1993; Clapham, D. E., Cell, 80, 259, 1995).
In order to study the signal transmission induced by IP
3
, a lot of IP
3
analogues have been synthesized (Li, W., et al., Nature, 392, 936, 1998; McCarren, M. et al., J. Neuron, 3, 461, 1989), and the structures of the IP
3
receptors and other IP
3
binding proteins have been examined (Mourey, R. J. et al., Biochemistry, 32, 1719, 1993). It has been reported that, even though the phosphate in the 1-position of IP
3
is modified, its binding affinity to the IP
3
receptor is not substantially affected (Schafer, R., et al., Biochem. J., 272, 817, 1990; Prestwich, G. D. et al., J. Am. Chem. Soc., 113, 1822, 1991). It is known that adenophostins, metabolites isolated from a culture of
Penicillium brevicompactum
, are most potent agonists to the IP
3
receptors (Takahashi, M., et al., J. Biol. Chem., 269, 369, 1994).
DISCLOSURE OF THE INVENTION
The inventors of the present invention conducted various studies to provide a novel IP
3
receptor ligand. As a result, they unexpectedly found that compounds having extremely high affinity to the IP
3
receptor can be provided by modifying the phosphate in the 1-position of IP
3
with a dye derivative or a fluorescent dye derivative such as malachite green and fluorescein. The present invention was achieved on the basis of the above findings.
The present invention thus provides compounds represented by the following general formula (I) or salts thereof:
wherein R represents a group represented by the following formula (A), (B) or (C):
wherein R
1
and R
2
independently represent a C
1-6
alkyl group; R
3
represents an amino group, a mono(C
1-6
alkyl)amino group, a di(C
1-6
alkyl)amino group, or a C
1-6
alkoxy group; and X- represents an anion, and n represents an integer of 2 to 5.
According to preferred embodiments of the present invention, provided are the aforementioned compounds or salts thereof, wherein the compounds represented by the general formula (I) are those represented by the following formula (I-1):
wherein R has the same meaning as that defined above; the aforementioned compounds or salts thereof, wherein R is a group represented by the formula (A) wherein R
1
and R
2
represent a methyl group, R
3
represents a dimethylamino group, and X- represents a chlorine ion, and n is 3; and the aforementioned compounds or salts thereof, wherein R is a group represented by the formula (A) wherein R
1
and R
2
represent a methyl group, R
3
represents a dimethylamino group and X- represents a chlorine ion, and n is 3.
From another aspect of the present invention, there are provided IP
3
receptor ligands which comprises a compound represented by the aforementioned general formula (I) or a salt thereof. IP
3
receptor can be denatured by binding the aforementioned IP
3
receptor ligand and then irradiating with light. Therefore, the IP
3
receptor ligands comprising the compound represented by the aforementioned general formula (I) or a salt thereof are useful as regents for denaturing the IP
3
receptor. The present invention also provides medicaments comprising the compound represented by the aforementioned general formula (I) or a salt thereof. These medicaments are useful as agents for prophylactic and/or therapeutic treatment of diseases resulting from supernumerary IP
3
or hyper-expression of the IP
3
receptor.
From still further aspect of the present invention, there are provided methods for denaturing the IP
3
receptor, which comprise the steps of binding the compound represented by the aforementioned general formula (I) or a salt thereof to the IP
3
receptor and then irradiating the result with light. The present invention also provides cells or cell extracts, of which IP
3
receptor is denatured, preferably by the aforementioned methods.
REFERENCES:
Habel et al, Feb. 1998, “Human osteoblast-like cells respond not only to the extracellular calcium concentration but also to its changing rate”, Eur. Biophys. Jol., vol. 27 pp 411-416 (1998).*
Berridge, M., Nature 361, pp. 315-325 (1993).
Clapham, D., Cell 80, pp. 259-268 (1995).
Li, W-h., et al., Nature 392, pp. 936-941 (1998).
McCarran, M., et al., Neuron 3, pp. 461-471 (1989).
Mourey, R., et al., Biochemistry 32, pp. 1719-1726 (1993).
Schäfer, R., et al., Biochem. J. 272, pp. 817-825 (1990).
Prestwich, G., et al., J. Am. Chem. Soc. 113, pp. 1822-1825 (1991).
Takahashi, M., et al., J. Biol. Chem. 269, pp. 369-372 (1994).
Strupish, J. et al., Biochem. J. 253, pp. 901-905 (1988).
Ozaki, S. et al., J. Chem. Soc. Perkins Trans. I, pp. 729-737 (1992).
Gigg, J., et al., J. Chem. Soc. Perkins Trans. I, pp. 423-429 (1987).
Bannawarth, W., and Trzeciak, A., Helvetica Chimica Acta 70, pp. 175-187 (1987).
Radenburg, T., et al., Biochem. J. 264, pp. 323-333 (1989).
Mignery, G., and Südhof, T. EMBO 9, pp. 3893-3898 (1990).
Yamada, N., et al., Biochem J. 302, pp. 781-790 (1994).
Hirose Kenzo
Iino Masamitsu
Inoue Takanari
Kikuchi Kazuya
Nagano Tetsuo
Covington Raymond
Greenblum & Bernstein P.L.C.
Nagano Tetsuo
Rotman Al
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