DOI: 10.1111/j.1471-4159.1993.tb03197.x. In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L‐690,330

In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L‐690,330

10.1111/j.1471-4159.1993.tb03197.x

Crossref journal-article

Wiley

Journal of Neurochemistry (311)

Abstract

Abstract: We have previously described the synthesis of bis‐phosphonate‐containing inhibitors of inositol monophosphatase. In the present study, a more detailed examination of the in vitro and in vivo properties of one of these compounds, L‐690,330, is described. L‐690,330 is a competitive inhibitor of inositol monophosphatase with a K1, depending on the source of IMPase, of between 0.2 and 2 μM. Although ∼1,000‐fold more potent in vitro than lithium, in muscarinic m1 receptor‐transfected Chinese hamster ovary cells prelabelled with [3H]inositol, L‐690,330 only produced 40% of the accumulation of [3H]inositol monophosphates achieved by lithium at the same concentration (10 mM), suggesting that the ability of L‐690,330 to cross the cell membrane is limited. Nevertheless, under conditions of cholinergic stimulation (100 mg/kg of pilocarpine s.c.), high doses of L‐690,330 were able to increase brain inositol(1)phosphate levels in vivo to three‐ to fourfold control levels. This effect was dose dependent (ED50= 0.3 mmol/kg s.c.) and was maximal after 1 h. In peripheral tissues, the effects of L‐690,330 on inositol(1)phosphate levels mimicked those of lithium both qualitatively and quantitatively. However, in the brain, the effects of L‐690,330 were much less than seen with lithium, consistent with the blood‐brain barrier restricting access of the polar L‐690,330 into the CNS, thereby further limiting entry of compound into cells in the brain. In the future, it may be possible to develop prodrugs of this compound, which circumvent many of the cell permeability problems inherent in bisphosphonate compounds.

Bibliography

Atack, J. R., Cook, S. M., Watt, A. P., Fletcher, S. R., & Ragan, C. I. (1993). In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate Lâ690,330. Journal of Neurochemistry, 60(2), 652â658. Portico.

Authors 5

John R. Atack (first)
Susan M. Cook (additional)
Alan P. Watt (additional)
Stephen R. Fletcher (additional)
C. Ian Ragan (additional)

References 26 Referenced 68

10.1111/j.1471-4159.1992.tb11031.x
10.1038/331440a0
10.1039/c39900000462 / J. Chem. Soc. Chem. Commun. / Identification of (1S)‐phosphoryloxy‐(2R, 4S)‐dihydroxycyclohexane as a potent inhibitor of inositol monophosphatase by Baker R. (1990)
BakerR. CarrickC. LeesonP. D. LennonI. C. andLivertonN. J.(1991)Design and synthesis of 6α‐substituted 2ß 4α‐dihydroxy‐1ß‐phosphoryloxycyclohexanes potent inhibitors of inositol monophosphatase.J. Chem. Soc. Chem. Commun.298–300. (10.1039/C39910000298)
10.1016/0003-2697(91)90271-T
10.1111/j.1471-4159.1985.tb07221.x
10.1042/bj2120473
10.1016/0092-8674(89)90026-3
10.1073/pnas.88.23.10634
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10.1016/S0021-9258(19)70391-3
10.1042/bj2640419
10.1111/j.1471-4159.1989.tb08566.x
10.1042/bj2670781
KulagowskiJ. J. BakerR. andFletcherS. R.(1991)Inhibitors of myo‐inositol monophosphatase containing methylenebisphosphonic acid as a replacement for a phosphate group.J. Chem. Soc. Chem. Commun.1649–1650. (10.1039/c39910001649)
10.1111/j.1471-4159.1980.tb09662.x
10.1042/bj2840749
10.1016/0165-6147(91)90581-C
10.1007/978-1-4612-3324-4_8
10.1042/bj2490143
10.1016/0006-8993(79)90617-6
{'key': 'e_1_2_2_24_1', 'first-page': '2639', 'article-title': 'Effects of lithium on phosphoinositide metabolism in vivo', 'volume': '45', 'author': 'Sherman W. R.', 'year': '1986', 'journal-title': 'Fed. Proc.'} / Fed. Proc. / Effects of lithium on phosphoinositide metabolism in vivo by Sherman W. R. (1986)
10.1017/S0033291700025836
10.1111/j.1471-4159.1989.tb01845.x
10.1073/pnas.87.24.9548

Dates

Type	When
Created	18 years, 11 months ago (Oct. 6, 2006, 12:01 a.m.)
Deposited	1 year, 10 months ago (Oct. 25, 2023, 3:58 p.m.)
Indexed	3 months, 2 weeks ago (May 21, 2025, 5:46 a.m.)
Issued	32 years, 7 months ago (Feb. 1, 1993)
Published	32 years, 7 months ago (Feb. 1, 1993)
Published Online	18 years, 11 months ago (Oct. 5, 2006)
Published Print	32 years, 7 months ago (Feb. 1, 1993)

Funders 0

None

BibTeX

@article{Atack_1993, title={In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L‐690,330}, volume={60}, ISSN={1471-4159}, url={http://dx.doi.org/10.1111/j.1471-4159.1993.tb03197.x}, DOI={10.1111/j.1471-4159.1993.tb03197.x}, number={2}, journal={Journal of Neurochemistry}, publisher={Wiley}, author={Atack, John R. and Cook, Susan M. and Watt, Alan P. and Fletcher, Stephen R. and Ragan, C. Ian}, year={1993}, month=feb, pages={652–658} }

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