ATPase inhibitors

For control of gastric acid secretion, the H2 antagonists have encountered competition from the potent -ATPase inhibitors such as... 

ATPase inhibitor. In such patients, inhibition of the sodium pump in the cells lining the blood vessel wall results in accumulation of sodium and calcium in these cells and the narrowing of the vessels to create hypertension. An 8-year study aimed at the isolation and identification of the agent responsible for these effects by researchers at the University of Maryland Medical School and the Upjohn Laboratories in Michigan recently yielded a surprising result. Mass spectrometric analysis of compounds isolated from many hundreds of gallons of blood plasma has revealed that the hypertensive agent is ouabain itself or a closely related molecule ... 

Gastric H,K-ATPase inhibitors Potassium competitive acid blockers... 

Cells are normally kept at osmotic (water activity) equilibrium by the action of the Na-pump. Inhibition of the pump with the specific Na -K -ATPase inhibitor, ouabain, causes cell swelling as does inhibition of it by hypothermia. The intracellular environment contains a high concentration of K (100 to 120 mM, in most mammalian cells), lower concentrations of Na (about 10 to 30 mM), and high... 

ATC A02BC02 A02BD04 Use antisecretory, gastric HYK -ATPase inhibitor... 

The transport of EDTA into a bacterial strain capable of its degradation has been examined (Witschel et al. 1997). Inhibition was observed with DCCD (ATPase inhibitor), nigericin (dissipates ApH), but not valinomycin (dissipates Av /), and was dependent on the stability constant of metal-EDTA complexes. 

GABA, heterocyclic analogues, 22 (1985) 67 GABAa receptor ligands, 36 (1999) 169 Gas-liquid chromatography and mass spectrometry, 12 (1975) 1 Gastric H /K -ATPase inhibitors, 31 (1994) 233... 

For the internalisation of metals, many examples exist for which transport may be coupled to an energy-dependent process, of which only a few are described here. For example, the well-studied (e.g. [276]) Na+/K+ channel transports 3Na+ out and 2K+ in for each ATP molecule that is hydrolysed [242]. Mg2+ influx (but likely not efflux) is highly regulated in eukaryotes [277]. ATPases have been implicated in certain cases of Fe [278] or Zn [90] uptake by phytoplankton. Finally, although Cd internalisation by a polychaete appeared to be energy independent, accumulation was increased rather than decreased in the presence of ATPase inhibitors, suggesting that the efflux system might depend upon ATP synthesis [279]. 

Results similar to those reported for co-conotoxin GVIA were obtained with the Na+, K+-ATPase inhibitor-I (10) J67 a 49 amino acid residue peptide containing four intramolecular disulfide bonds (Scheme 5)J681 Even in this case the addition of redox reagents to the oxidation buffer had a minor effect on the product distribution. 

The reduced form of Na+, K+-ATPase inhibitor-I (10) was obtained by treatment of the protected peptide synthesized by the soln procedure with HF, followed by reaction with Hg(OAc)2. After purification of the crude product on Sephadex G-25, the reduced peptide (110 mg) was dissolved in 0.1 M NH4OAc buffer (1L, pH 7.8) at a peptide concentration of 0.018 mM and then stirred at rt. After 24 h, the major peak in the HPLC, which coeluted with the natural product, corresponded to 55% of the product distribution. The mixture was acidified to pH 3 with AcOH and 10 was purified by RP-HPLC. When the oxidation was carried out in the presence redox reagents at a peptide/GSH/GSSG ratio of 1 100 10, after 24 h the major oxidation product increased to 69%. The mixture was acidified with AcOH and the product (10) isolated by preparative HPLC yield 20%. The product was characterized by MALDI-TOF-MS and amino acid analysis a combination of enzymatic peptide mapping and synthetic approaches were applied to assign the cystine connectivities. 

Okamoto, Y. Ojika, M. Sakagami, Y. (1999) lanthaan A, a dimoic polybrominated benzofuran as a Na,K-ATPase inhibitor from a marine sponge, lanthella sp. Tetrahedron Lett., 40, 507-10. 

Other proton pump inhibitors e.g., lansoprazole is more potent than omeprazole and has higher bioavailability, rapid onset of action and longer duration of action. Pantoprazole is the new H+K+ATPase inhibitor with similar properties and action to omeprazole. 

This strategy has already been found useful in natural product synthesis. In the course of a synthesis of V-ATPase inhibitor oximidine HI, John Porco of Boston University has described (Angew. Chem. Ini. Ed. 2004,43, 3601) the cyclization of 7 to 8. In the absence of the pententyl director, the initial complexation of the Ru catalyst was with the 1,3-diene, leading to allylidene complex and so effectively killing the catalyst. In this case, the Hoveyda catalyst 8 provided a cleaner product than G2 did. 

A hexaprenyl-hydroquinone sulfate (395) was identified as an H+/K+-ATPase inhibitor from a Japanese species of Dysidea [339]. Sarcotragus spinulosus from deep water contained the Na+/K+-ATPase inhibitors sarcochromenol sulfates A-C (396-398) and sarcohydroquinone sulfates A-C (399-401) [340]. The structures were determined by spectral data analysis of the natural products and of derivatives. 

Iantherans A (516) and B (517) are dimeric tetrabrominated benzofuran derivatives that were isolated from an Australian Ianthella species. The structures were determined by spectroscopic and chemical methods. Iantheran A (516) includes a (Z,Z)-1,3-butadiene moiety, whereas iantheran B (517) is the geometric isomer possessing a (Z, )- 1,3-butadiene moiety. Both compounds were Na+/K+-ATPase inhibitors [434,435]. Ianthesines C (518) and D (519) showed potent Na+/K+-... 

Figure 30-16 Structures of some neurotoxins that affect ion channels. Other neurotoxins include the Na+, K+-ATPase inhibitor ouabain (Fig. 22-12), batrachotoxin (Fig. 22-12), and picrotoxin (Fig. 22-4). The structure of a scorpion toxin is from Almassy et al.,i9ia that of to conotoxin is from Pallaghy et al.,i35 and that of brevetoxin is redrawn after Shimizu et al.i36...

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