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Chemical Compound Review

CHEMBL541543     N-(1-adamantyl)-N'- cyclohexyl-morpholine-4...

Synonyms: AG-G-03256, P0248_SIGMA, SureCN10619504, SureCN10619509, PNU-37883A, ...
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Disease relevance of Lopac-P-0248


High impact information on Lopac-P-0248

  • We suggest that the U-37883 binding site represents a functional receptor that mediates the KATP channel antagonism and natriuresis observed with this class of compounds [3].
  • In the present study, the binding characteristics of the U-37883 receptor were investigated using pig kidney cortex microsomes [3].
  • U-37883 (4-morpholinecarboximidine-N-1-adamantyl-N-cyclohexyl), a known blocker of ATP-sensitive K+ (KATP) channels, produces natriuresis/diuresis in vivo by a direct effect on the kidney [3].
  • Studies with analogs of U-37883A showed that U-52090A inhibited KATP current and displaced [3H]U-37883 from its binding site with similar potencies [1].
  • The available data collectively suggest that U-37883A is a more selective blocker of the follicular KATP channel, which is very similar to that in smooth muscle, than of the pancreatic beta cell KATP channel [1].

Biological context of Lopac-P-0248

  • U-37883A alone produced inhibition in the concentration range of 0.5 to 5 microM, with the U-37883A IC50 ranging from 0.78 to 1.4 microM [4].
  • Effects of K+ channel modulation on glomerular filtration rate and electrolyte excretion were studied using the adenosine-triphosphate- (ATP)-sensitive K+ channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U-37883A) in conscious rats previously equipped with catheters for clearance studies [5].
  • U-37883A, which does not inhibit P1075 binding, is one of the most potent blockers of P1075-induced 86Rb+ efflux yet described but is relatively weak as an inhibitor of P1075-mediated vasorelaxation [6].
  • Guanidine derivative U-37883A, inhibits mitochondrial K+ uniport [7].
  • Higher doses of U-37883A (16-32 mg/kg) fatally reduced MAP (-84%), heart rate (HR; -57%) and LV contractility (-72%) [8].

Anatomical context of Lopac-P-0248


Associations of Lopac-P-0248 with other chemical compounds

  • The diuretic profile of 1 and its 1-adamantyl analog (U-37883A, 4) was confirmed orally in dogs, when they were less potent than standard diuretics but showed furosemide-like natriuresis at > or = 100 mumol/kg [11].
  • This study describes the in vitro and in vivo characteristics of a guanidine 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydroc hloride (U-37883A), as an antagonist of vascular ATP-sensitive K+ channels (KATP) [12].
  • These observations suggest that U-37883A enhances phosphatidylserine synthesis indirectly by acting on calcium transport, thus affecting calcium concentration within the lumen of endoplasmic reticulum membranes [10].
  • Furthermore, rats were given intravenous injection of ATP-sensitive K+ channel blocker, either PNU-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl) at a concentration of 10 mg/kg or glibenclamide at 30 mg/kg [13].
  • P1075-stimulated 86Rb+ efflux, a qualitative measure of K(ATP) channel opening, was inhibited by U-37883A and torasemide with IC50 values of 0.06 and 130 microM, respectively; furosemide induced only a small (23%) inhibition [6].

Gene context of Lopac-P-0248

  • Vasodilator responses to hCGRP, hAmylin, and hADM were not altered by the vascular selective K+(ATP) channel antagonist U-37883A [14].
  • This inward current was significantly inhibited by PNU-37883A and by a specific anti-Kir6.1 antibody [15].
  • 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group [16].
  • 3. Channels containing Kir6.1/SUR2B were more sensitive to inhibition by PNU-37883A than those containing Kir6.2/SUR2B (mean fractional inhibition: 0.70, cf. 0.07) [17].
  • Different molecular sites of action for the KATP channel inhibitors, PNU-99963 and PNU-37883A [18].

Analytical, diagnostic and therapeutic context of Lopac-P-0248


  1. Functional receptors in Xenopus oocytes for U-37883A, a novel ATP-sensitive K+ channel blocker: comparison with rat insulinoma cells. Guillemare, E., Honore, E., De Weille, J., Fosset, M., Lazdunski, M., Meisheri, K. Mol. Pharmacol. (1994) [Pubmed]
  2. Cardiovascular interactions characterizing the vasodilator components of nicorandil in conscious dogs. Humphrey, S.J., Schwende, F.J. J. Cardiovasc. Pharmacol. (1995) [Pubmed]
  3. Receptor binding characterization in kidney membrane of [3H]U-37883, a novel ATP-sensitive K+ channel blocker with diuretic/natriuretic properties. Meisheri, K., Fosset, M., Humphrey, S., Lazdunski, M. Mol. Pharmacol. (1995) [Pubmed]
  4. Synergistic effects of glyburide and U-37883A, two structurally different vascular ATP-sensitive potassium channel antagonists. Ohrnberger, C.E., Khan, S.A., Meisheri, K.D. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  5. Effects of a K+ channel blocker on glomerular filtration rate and electrolyte excretion in conscious rats. Ludens, J.H., Clark, M.A., Lawson, J.A. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  6. Interaction of the diuretics torasemide and U-37883A with the K(ATP) channel in rat isolated aorta. Löffler-Walz, C., Quast, U. Naunyn Schmiedebergs Arch. Pharmacol. (1998) [Pubmed]
  7. Guanidine derivative U-37883A, inhibits mitochondrial K+ uniport. Szewczyk, A., Wójcik, G., Jabłonowska, A., Nałecz, n.u.l.l. Polish journal of pharmacology. (1995) [Pubmed]
  8. Cardiovascular effects of the K-ATP channel blocker U-37883A and structurally related morpholinoguanidines. Humphrey, S.J., Smith, M.P., Cimini, M.G., Buchanan, L.V., Gibson, J.K., Khan, S.A., Meisheri, K.D. Methods and findings in experimental and clinical pharmacology. (1996) [Pubmed]
  9. Inhibition of vascular K(ATP) channels by U-37883A: a comparison with cardiac and skeletal muscle. Wellman, G.C., Barrett-Jolley, R., Köppel, H., Everitt, D., Quayle, J.M. Br. J. Pharmacol. (1999) [Pubmed]
  10. An antagonist of ATP-regulated potassium channels, the guanidine derivative U-37883A, stimulates the synthesis of phosphatidylserine in rat liver endoplasmic reticulum membranes. Makowski, P., Szewczyk, A., Jasińska, R., Pikuła, S. FEBS Lett. (1997) [Pubmed]
  11. Synthesis and diuretic activity of alkyl- and arylguanidine analogs of N,N'-dicyclohexyl-4-morpholinecarboxamidine in rats and dogs. Perricone, S.C., Humphrey, S.J., Skaletzky, L.L., Graham, B.E., Zandt, R.A., Zins, G.R. J. Med. Chem. (1994) [Pubmed]
  12. 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydrochloride (U-37883A): pharmacological characterization of a novel antagonist of vascular ATP-sensitive K+ channel openers. Meisheri, K.D., Humphrey, S.J., Khan, S.A., Cipkus-Dubray, L.A., Smith, M.P., Jones, A.W. J. Pharmacol. Exp. Ther. (1993) [Pubmed]
  13. K+ loading, but not Na+ loading, and blockade of ATP-sensitive K+ channels augment renal kallikrein secretion. Fujita, T., Hayashi, I., Kumagai, Y., Inamura, N., Majima, M. Immunopharmacology (1999) [Pubmed]
  14. Analysis of responses to hAmylin, hCGRP, and hADM in isolated resistance arteries from the mesenteric vascular bed of the rat. Champion, H.C., Pierce, R.L., Bivalacqua, T.J., Murphy, W.A., Coy, D.H., Kadowitz, P.J. Peptides (2001) [Pubmed]
  15. Mediation of the effect of nicotine on Kir6.1 channels by superoxide anion production. Hanna, S.T., Cao, K., Sun, X., Wang, R. J. Cardiovasc. Pharmacol. (2005) [Pubmed]
  16. Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats. Fujita, T., Hayashi, I., Kumagai, Y., Inamura, N., Majima, M. Br. J. Pharmacol. (1999) [Pubmed]
  17. Molecular analysis of the subtype-selective inhibition of cloned KATP channels by PNU-37883A. Kovalev, H., Quayle, J.M., Kamishima, T., Lodwick, D. Br. J. Pharmacol. (2004) [Pubmed]
  18. Different molecular sites of action for the KATP channel inhibitors, PNU-99963 and PNU-37883A. Cui, Y., Tinker, A., Clapp, L.H. Br. J. Pharmacol. (2003) [Pubmed]
  19. Multiple actions of U-37883A, an ATP-sensitive K+ channel blocker, on membrane currents in pig urethra. Tomoda, T., Yunoki, T., Naito, S., Ito, Y., Teramoto, N. Eur. J. Pharmacol. (2005) [Pubmed]
  20. D-[Ala2]endomorphin 2 and endomorphin 2 have nitric oxide-dependent vasodilator activity in rats. Champion, H.C., Kadowitz, P.J. Am. J. Physiol. (1998) [Pubmed]
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