L-690,330

L-690,330 is a competitive inhibitor of inositol monophosphatase (IMPase) with a Ki value of between 0.2 and 2 μM depending on the source of IMPase [1].

In the phosphatidylinositol (PI) cycle cell signalling pathway, IMPase is involved as a key enzyme. Inositol monophosphates, inositol(1)phosphate [Ins(l)P], inositol(3)phosphate [Ins(3)P], and inositol(4)phosphate [Ins(4)P] are hydrolyzed by IMPase and produce free inositol. Free inositol can then be used to synthesize PI [1].

In carbachol-stimulated m1 CHO cells, the treatment with L-690,330 alone did not increase the amount of [3H]InsP1. In the absence of L-690,330, the treatment with carbachol alone increased levels of [3H]InsP1, resulted in levels ranging from 20 to 100% above basal [3H]InsP1 levels. In the presence of carbachol, lithium at 10 mM increased the amount of [3H]InsP1 by approximate five folds (relative to [3H]InsP1 levels in carbachol-stimulated cells) and the EC50 value of this effect was about 1 mM. In carbachol-stimulated cells, L-690,330 at 10 mM resulted in only ~40% of the maximum response seen in the case with lithium treatment [1].

In mouse brains, in the absence of L-690,330, pilocarpine produced approximately doubled levels of Ins(1)P. In the absence of pilocarpine, L-690,330 did not affect Ins(1)P levels. Under pilocarpine-stimulated conditions, treatment with L-690,330 resulted in a pronounced accumulation of Ins(1)P, with the maximum level observed 1 h after injection. The maximum was of an approximate four-fold elevation [1].

Reference:
[1].  Atack JR, Cook SM, Watt AP, et al. In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L-690,330. Journal of neurochemistry, 1993, 60(2): 652-658.

Effects of L-690,488, a prodrug of the bisphosphonate inositol monophosphatase inhibitor L-690,330, on phosphatidylinositol cycle markers.[Pubmed:8035344]

J Pharmacol Exp Ther. 1994 Jul;270(1):70-6.

In order to enhance the entry into cells of L-690,330, a bisphosphonate inhibitor of inositol monophosphatase (IMPase; a key, enzyme in the phosphatidylinositol (Pl) cell signaling pathway), the tetrapivaloyloxymethyl ester prodrug, L-690,488 [tetrapivaloyloxymethyl 1-(4-hydroxyphenoxy)ethane-1,1-bisphosphonate], was synthesized. The effects of L-690,488 were studied in cholinergically (carbachol)-stimulated rat cortical slices and Chinese hamster ovary cells stably transfected with the human muscarinic m1 receptor (m1 CHO cells). The accumulation of [3H]inositol monophosphates or [3H]cytidine monophosphorylphosphatidate ([3H]CMP-PA) after [3H]inositol or [3H]cytidine prelabeling, respectively, and inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate mass were measured. In rat cortical slices and m1 CHO cells, the maximum response and time course of accumulation of [3H]inositol monophosphates for L-690,488 and lithium were similar. However, the concentrations of L-690,488 required to produce these effects (EC50 values of 3.7 +/- 0.9 and 1.0 +/- 0.2 microM in cortical slices and m1 CHO cells, respectively) were much lower than with lithium (0.3-1.5 mM). Likewise, the time course and maximum accumulation of [3H] CMP-PA in L-690,488-treated m1 CHO cells was similar to lithium but L-690,488 was again much more potent (EC50 values = 3.5 +/- 0.3 microM and 0.52 +/- 0.03 mM for L-690,488 and lithium, respectively). In addition, L-690,488 attenuated the carbachol-induced elevation of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in m1 CHO cells, an effect reported previously with lithium. These results are all consistent with L-690,488 and lithium both depleting intracellular inositol as a consequence of inhibition of IMPase. That these effects of L-690,488 on the PI cycle are indeed due to inositol depletion is shown by the observation that the effects of L-690,488 on CMP-PA accumulation could be overcome by addition of exogenous myo-inositol (EC50 = 1.7 +/- 0.5 mM). These data show that inhibition of IMPase produces effects on the PI cycle comparable to lithium. As a corollary, the effects of lithium on the PI cycle are therefore consistent with its major mechanism of action being inhibition of IMPase.

The inositol monophosphatase inhibitor L-690,330 affects pilocarpine-behavior and the forced swim test.[Pubmed:23344554]

Psychopharmacology (Berl). 2013 Jun;227(3):503-8.

RATIONALE: Lithium has been a standard pharmacological treatment for bipolar disorder over the last 60 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. Attenuation of the phosphatidylinositol signal transduction pathway as a consequence of inhibition of inositol monophosphatase (IMPase) has been proposed as one of the possible mechanisms for lithium-induced mood stabilization. OBJECTIVES: The objective was to study the behavioral effect of the specific competitive IMPase inhibitor L-690,330 in mice in the lithium-sensitive pilocarpine-induced seizures paradigm and the forced swim test (FST). METHODS: The inhibitor was administered intracerebroventricularly in liposomes. RESULTS: L-690,330 increased the sensitivity to subconvulsive doses of pilocarpine and decreased immobility time in the FST. CONCLUSIONS: It is possible that the behavioral effects of lithium in the pilocarpine-induced seizures and in the FST are mediated through the inhibition of IMPase, but reversal of the inhibitor's effect with intracerebroventricular inositol would be an important further step in proof.

In vitro and in vivo inhibition of inositol monophosphatase by the bisphosphonate L-690,330.[Pubmed:8380439]

J Neurochem. 1993 Feb;60(2):652-8.

We have previously described the synthesis of bisphosphonate-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 Ki, depending on the source of IMPase, of between 0.2 and 2 microM. Although approximately 1,000-fold more potent in vitro than lithium, in muscarinic ml 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(l)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(l)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.

Chemical modulators of autophagy as biological probes and potential therapeutics.[Pubmed:21164513]

Nat Chem Biol. 2011 Jan;7(1):9-17.

Autophagy is an evolutionarily conserved mechanism for protein degradation that is critical for the maintenance of homeostasis in man. Autophagy has unexpected pleiotropic functions that favor survival of the cell, including nutrient supply under starvation, cleaning of the cellular interior, defense against infection and antigen presentation. Moreover, defective autophagy is associated with a diverse range of disease states, including neurodegeneration, cancer and Crohn's disease. Here we discuss the roles of mammalian autophagy in health and disease and highlight recent advances in pharmacological manipulation of autophagic pathways as a therapeutic strategy for a variety of pathological conditions.

Lithium induces autophagy by inhibiting inositol monophosphatase.[Pubmed:16186256]

J Cell Biol. 2005 Sep 26;170(7):1101-11.

Macroautophagy is a key pathway for the clearance of aggregate-prone cytosolic proteins. Currently, the only suitable pharmacologic strategy for up-regulating autophagy in mammalian cells is to use rapamycin, which inhibits the mammalian target of rapamycin (mTOR), a negative regulator of autophagy. Here we describe a novel mTOR-independent pathway that regulates autophagy. We show that lithium induces autophagy, and thereby, enhances the clearance of autophagy substrates, like mutant huntingtin and alpha-synucleins. This effect is not mediated by glycogen synthase kinase 3beta inhibition. The autophagy-enhancing properties of lithium were mediated by inhibition of inositol monophosphatase and led to free inositol depletion. This, in turn, decreased myo-inositol-1,4,5-triphosphate (IP3) levels. Our data suggest that the autophagy effect is mediated at the level of (or downstream of) lowered IP3, because it was abrogated by pharmacologic treatments that increased IP3. This novel pharmacologic strategy for autophagy induction is independent of mTOR, and may help treatment of neurodegenerative diseases, like Huntington's disease, where the toxic protein is an autophagy substrate.

L-690330 is a competitive inhibitor of inositol monophosphatase (IMPase) with Kis of 0.27 and 0.19 μM for recombinant human and bovine IMPase, 0.30 and 0.42 μM for human and bovine frontal cortex IMPase, respectively. L-690330 exhibits 10-fold more sensitive than mouse and rat IMPase.

L-690,330,142523-38-4,Natural Products,Inositol Phosphatases, buy L-690,330 , L-690,330 supplier , purchase L-690,330 , L-690,330 cost , L-690,330 manufacturer , order L-690,330 , high purity L-690,330