Antiulcer agents. 5. Inhibition of gastric H+/K+-ATPase by substituted imidazo[1,2-a]pyridines and related analogs and its implication in modeling the high affinity potassium ion binding site of the gastric proton pump enzyme

Kaminski, James J.; Wallmark, Björn; Briving, Carin; Andersson, Bo

doi:10.1021/jm00106a008

Cited by 101 publications

(52 citation statements)

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“…4 A). To test whether K+ was absorbed via H+/K+-ATPase, we measured net transport across monolayers exposed to mucosal SCH 28080, a specific inhibitor of H+/K+-ATPase in some epithelial cells (25)(26)(27)(28). Fig.…”

Section: Resultsmentioning

confidence: 99%

Fluid and electrolyte transport by cultured human airway epithelia.

Smith

Welsh²

1993

J. Clin. Invest.

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An understanding of the fluid and electrolyte transport properties of any epithelium requires knowledge of the direction, rate, and regulation of fluid transport and the composition of the fluid. Although human airway epithelia likely play a key role in controlling the quantity and composition of the respiratory tract fluid, evidence for such a role is not available. To obtain such knowledge, we measured fluid and electrolyte transport by cultured human nasal epithelia. Under basal conditions we found that epithelia absorbed Na+ and fluid; both processes were inhibited by addition of amiloride to the mucosal surface. These data suggest that active Na+ absorption is responsible for fluid absorption. Interestingly, Na+ absorption was not accompanied by the net absorption of Cl ; some other anion accompanied Na+. The combination of cAMP agonists and mucosal amiloride stimulated the secretion of NaCl-rich fluid. But surprisingly, the response to cAMP agonists in the absence of amiloride showed substantial intersubject variability: cAMP stimulated fluid secretion across some epithelia, for others, cAMP stimulated fluid absorption. The explanation for the differences in response is uncertain, but we speculate that the magnitude of apical membrane Na+ conductance may modulate the direction of fluid transport in response to cAMP. We also found that airway epithelia secrete H+ and absorb K+ under basal conditions; both processes were inhibited by cAMP agonists. Because the H+/K+-ATPase inhibitor, SCH 28080, inhibited K+ absorption, an apical membrane H+/K+-ATPase may be at least partly responsible for K+ and H+ transport. However, H+/K+ exchange could not entirely account for the luminal acidification. The finding that cAMP agonists inhibited luminal acidification may be explained by the recent finding that cAMP increases apical HCO3 conductance. These results provide new insights into how the intact airway epithelium may modify the composition of the respiratory tract fluid. (J.

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Section: Resultsmentioning

confidence: 99%

Fluid and electrolyte transport by cultured human airway epithelia.

Smith

Welsh²

1993

J. Clin. Invest.

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“…An important goal is accurate description of the high-affinity binding site of these reversible inhibitors as the foundation for structure-based drug design. The active conformation of SCH28080 has been identified (9), and the rotationally restricted naphthyridine, Byk99, that mimics this structure was therefore used in combination with homology modeling to define inhibitor access and binding in a new E 2 P model of the H,K ATPase.…”

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confidence: 99%

Analysis of the Gastric H,K ATPase for Ion Pathways and Inhibitor Binding Sites

2007

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New models of the gastric H,K ATPase in the E 1 K and E 2 P states are presented as the first structures of a K + counter-transport P 2 -type ATPase exhibiting ion entry and exit paths. Homology modeling was first used to generate a starting conformation from the srCa ATPase E 2 P form (PDB code 1wpg) that contains bound MgADP. Energy minimization of the model showed a conserved adenosine site but nonconserved polyphosphate contacts compared to the srCa ATPase. Molecular dynamics was then employed to expand the luminal entry sufficiently to allow access of the rigid K + competitive naphthyridine inhibitor, Byk99, to its binding site within the membrane domain. The new E 2 P model had increased separation between transmembrane segments M3 through M8, and addition of water in this space showed not only an inhibitor entry path to the luminal vestibule but also a channel leading to the ion binding site. Addition of K + to the hydrated channel with molecular dynamics modeling of ion movement identified a pathway for K + from the lumen to the ion binding site to give E 2 K. A K + exit path to the cytoplasm operating during the normal catalytic cycle is also proposed on the basis of an E 1 K homology model derived from the E 1 2Ca 2+ form of the srCa ATPase (PDB code 1su4). Autodock analyses of the new E 2 P model now correctly discriminate between high-and low-affinity K + competitive inhibitors. Finally, the expanded luminal vestibule of the E 2 P model explains high-affinity ouabain binding in a mutant of the H,K ATPase P 2 -type ATPases (ion pumps) catalyze active ion transport by coupling autophosphorylation and dephosphorylation to ion movement across lipid bilayers. The Na,K ATPases and the gastric H,K ATPase couple outward transport of sodium or protons to the inward transport of potassium. They are distinguished from the other members of this family by the presence of a glycosylated β subunit tightly bound to the larger catalytic (α) subunit and by the need for K + on their luminal surface for completion of the catalytic cycle. There is about 62% homology between their α subunits and about 35% homology between the gastric β subunit and the Na,K ATPase β 2 isoform (1). The α subunits contain the known binding sites for ATP, ions, and inhibitors. Several avenues of research have defined the biochemical features of the shared transport mechanism (2). Transport is achieved through a series of conformational transitions which alternatively bind the transported ions from the cytoplasm in the E 1 form or from the lumen after autophosphorylation from ATP to give the E 2 P conformer. Conversion to E 2 P is associated with export of the outbound cation with generation of luminal acid in the case of the H,K ATPase. For Na,K and H,K ATPases binding of potassium activates dephosphorylation to give a state with tightly bound ion (E 2 K occluded) in equilibrium with † Supported in part by the U.S. Veterans Administration and NIH Grants DK46917, DK53462, and DK58333. *Corresponding author. . kmunson@ucla.edu. ‡ David ...

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“…The cyclazine derivatives (4a-h) synthesised were analysed for IR.UV, 1 HNMR, 13 C NMR and mass spectral techniques. The cycl[3.2.2]azine products (4a-h) were obtained within 2-5 min in 20-80% yield.…”

Section: Resultsmentioning

confidence: 99%

“…]azine systems are tricyclic aromatic heterocycles with nitrogen as the central atom common to three rings and they are widely accepted due to their interesting physical and chemical properties [9]- [10]. Among cyclazine derivatives, tricyclic fused imidazo [1, 2-a]pyridines bridged between the C(3) and C(5) positions would be of particular interest because an imidazo[1, 2-a]pyridine ring system has popularly been utilized as a pharrmacophore for therapeutic drugs [11]- [13] and as biochemical fluorescent marker [14] due to its strong fluorescence [15]. The important characteristic feature of the cycl[3.2.2] azine is in the fact that the central nitrogen atom is nonbasic, indicating its pi-electrons are completely involved in the aromatic pi-electron system..…”

Section: Introductionmentioning

confidence: 99%