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Chemical Compound Review

CHEMBL25554     2-(2,6-dimethoxyphenoxy)-N- (7,10...

Synonyms: AGN-PC-00LZ3G, SureCN800982, BSPBio_002490, KBioGR_001646, KBioSS_002313, ...
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Disease relevance of WB 4101

  • Automatic arrhythmias induced by alpha 1-adrenergic stimulation during simulated ischemia may be attributed to a specific alpha 1-adrenergic receptor subtype that is blocked by WB 4101 [1].
  • Intrathecal injection of the alpha2-adrenoceptor antagonist yohimbine did not alter the hyperalgesic effect produced by the 7.5 nmol dose of morphine, but the alpha1 antagonist WB4101 reversed the hyperalgesia and produced antinociception that lasted for nearly 30 min [2].
  • Evoked mydriasis was significantly antagonized by both WB-4101 and 5-methylurapidil but not by BMY-7378 [3].
  • Furthermore, subtype specific antagonism of alpha1A-adrenoceptors by WB 4101 clearly reduced the occurrence of ventricular fibrillation in a concentration-dependent manner (0.01-1 micromol/l) from 66% to 17% [4].
  • In conclusion, evidence is presented of novel, direct protective effects of prazosin and WB 4101 against tetanic contracture following modified Na+ channel function and Ca2+ loading provoked by veratrine [5].

Psychiatry related information on WB 4101


High impact information on WB 4101

  • We have quantified relative potencies of tricyclic antidepressants in competing for the binding of 3H-labeled WB-4101 to alpha-noradrenergic receptor sites in rat brain membranes [7].
  • In conclusion, the increase in abnormal automaticity in ischemic Purkinje fibers depends on a WB 4101-sensitive alpha 1-adrenergic receptor subtype whose actions are transduced by a PTX-sensitive 41-kd G protein and are not blocked by ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)[8]
  • In contrast, WB 4101 selectively antagonized the NE-induced increase in automaticity in both age groups [9].
  • In COS-7 cells transfected with cDNAs encoding the three rat alpha 1-ARs, WB-4101 and benoxathian had similar binding affinities for the alpha 1a/d-AR and the alpha 1c-AR and 10-fold lower affinities for the alpha 1b-AR [10].
  • WB 4101 was 1000-fold more potent in inhibiting the [3H]InsP response in renal cells than hepatocytes; however, some of this difference was due to rapid metabolism of WB 4101 by hepatocytes [11].

Chemical compound and disease context of WB 4101

  • These results suggest the alpha1-adrenoceptor subtype blocked by chloroethylclonidine, but not that blocked by WB4101, is capable of increasing the incidence of lethal arrhythmias that occur at rapid atrial rates during ischemia [12].
  • These results suggest that NAN-190 is a pure antagonist of 8-OH-DPAT-induced hypothermia in rats and that BMY 7378 and WB 4101 are, respectively, a partial agonist and an agonist in this test.(ABSTRACT TRUNCATED AT 250 WORDS)[13]
  • Tetrodotoxin (TTX), prazosin, WB 4101 and R 56865 (0.1-10 microM) prevented tetanic contracture elicited by veratrine (100 micrograms/ml) at concentrations which were significantly lower than those which decreased active tension development [5].
  • We tested whether alpha 1A-AR stimulation by endogenous catecholamines, released during ischaemia, could modulate reperfusion arrhythmias, using as pharmacological tools the selective alpha 1A-AR antagonists abanoquil (UK52046) and WB4101 [14].

Biological context of WB 4101

  • The proportions of binding sites inactivated by 10 microM CEC under hypotonic conditions were quantitatively similar to and correlated significantly (p less than 0.01) with the proportion having a low affinity for WB 4101 [15].
  • Competitive binding studies with [3H]prazosin and compounds [5-methylurapidil, (+)-niguldipine, WB4101, and oxymetazoline] that distinguish high affinity (alpha 1a) and low affinity (alpha 1b) sites indicated that rat renal cortical membranes contain about 50% of each class of site [16].
  • Norepinephrine stimulated [3H]inositol monophosphate production severalfold; this was blocked by alpha 1-adrenergic antagonists, including prazosin, WB 4101, and phenoxybenzamine, but by neither an alpha 2- nor a beta-adrenergic antagonist, confirming that an alpha 1-adrenoceptor is involved in the regulation of phosphatidylinositol hydrolysis [17].
  • Structure-activity relationships for prazosin and WB 4101 analogues as alpha 1-adrenoreceptor antagonists [18].
  • The alpha-1 antagonist WB-4101 (dimethyloxyphenoxy-ethylamino-methyl benzo-1,4-dioxan) was the most potent inhibitor of PHE in lesioned rats with an IC50 of 125 nM, 110 times lower than that of prazosin (14 microM); yohimbine and propranolol, respectively, alpha-2 and beta-antagonists caused inhibition only at very high concentrations [19].

Anatomical context of WB 4101

  • Serotonin exhibits high affinity (Ki = 2.5 nM) and monophasic competition for [3H] WB4101 binding in cerebral cortex [20].
  • Pretreatment of hippocampus and vas deferens with CEC caused a loss of all low affinity WB 4101-binding sites, leaving only high affinity sites [15].
  • After correction for metabolism, WB 4101 was still 11-fold more potent in inhibiting norepinephrine-stimulated [3H]InsP formation in hepatocytes (alpha 1b) than in CEC-pretreated renal cells (alpha 1a) [11].
  • WB4101 (1)-related compounds 5-10 were synthesized, and their biological profile at alpha(1)-adrenoreceptor (AR) subtypes and 5-HT(1A) serotoninergic receptors was assessed by binding assays in Chinese hamster ovary and HeLa cell membranes expressing the human cloned receptors [21].
  • Spiroxatrine and 2-(2,6-dimethoxyphenoxyethyl)aminomethyl- 1,4-benzodioxane (WB 4101) which bind to 5-HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin-stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively [22].

Associations of WB 4101 with other chemical compounds


Gene context of WB 4101


Analytical, diagnostic and therapeutic context of WB 4101


  1. Abnormal automatic rhythms in ischemic Purkinje fibers are modulated by a specific alpha 1-adrenergic receptor subtype. Anyukhovsky, E.P., Rosen, M.R. Circulation (1991) [Pubmed]
  2. Microinjection of morphine in the A7 catecholamine cell group produces opposing effects on nociception that are mediated by alpha1- and alpha2-adrenoceptors. Holden, J.E., Schwartz, E.J., Proudfit, H.K. Neuroscience (1999) [Pubmed]
  3. alpha(1A)-adrenoceptors mediate sympathetically evoked pupillary dilation in rats. Yu, Y., Koss, M.C. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  4. Influence of alpha- and beta-adrenoceptor antagonists on ventricular fibrillation in ischemic rat hearts. Tölg, R., Kurz, T., Ungerer, M., Schreieck, J., Görge, B., Richardt, G. Naunyn Schmiedebergs Arch. Pharmacol. (1997) [Pubmed]
  5. Veratrine-induced tetanic contracture of the rat isolated left atrium. Evidence for novel direct protective effects of prazosin and WB4101. Le Grand, B., Marty, A., Vieu, S., Talmant, J.M., John, G.W. Naunyn Schmiedebergs Arch. Pharmacol. (1993) [Pubmed]
  6. Antinociception produced by microinjection of morphine in the rat periaqueductal gray is enhanced in the foot, but not the tail, by intrathecal injection of alpha1-adrenoceptor antagonists. Fang, F., Proudfit, H.K. Brain Res. (1998) [Pubmed]
  7. Tricyclic antidepressants: therapeutic properties and affinity for alpha-noradrenergic receptor binding sites in the brain. U'Prichard, D.C., Greenberg, D.A., Sheehan, P.P., Snyder, S.H. Science (1978) [Pubmed]
  8. Positive chronotropic responses induced by alpha 1-adrenergic stimulation of normal and "ischemic" Purkinje fibers have different receptor-effector coupling mechanisms. Anyukhovsky, E.P., Rybin, V.O., Nikashin, A.V., Budanova, O.P., Rosen, M.R. Circ. Res. (1992) [Pubmed]
  9. Specific alpha 1-adrenergic receptor subtypes modulate catecholamine-induced increases and decreases in ventricular automaticity. del Balzo, U., Rosen, M.R., Malfatto, G., Kaplan, L.M., Steinberg, S.F. Circ. Res. (1990) [Pubmed]
  10. The rat homologue of the bovine alpha 1c-adrenergic receptor shows the pharmacological properties of the classical alpha 1A subtype. Laz, T.M., Forray, C., Smith, K.E., Bard, J.A., Vaysse, P.J., Branchek, T.A., Weinshank, R.L. Mol. Pharmacol. (1994) [Pubmed]
  11. Alpha 1-adrenergic receptor subtypes and formation of inositol phosphates in dispersed hepatocytes and renal cells. Han, C.D., Wilson, K.M., Minneman, K.P. Mol. Pharmacol. (1990) [Pubmed]
  12. Chloroethylclonidine increases the incidence of lethal arrhythmias during coronary occlusion in anesthetized dogs. Geller, J.C., Cua, M., Prieto, L., Guo, S.D., Danilo, P., Rosen, M.R. Eur. J. Pharmacol. (1995) [Pubmed]
  13. The effect of putative 5-HT1A receptor antagonists on 8-OH-DPAT-induced hypothermia in rats and mice. Moser, P.C. Eur. J. Pharmacol. (1991) [Pubmed]
  14. Effects of selective alpha 1A-adrenoceptor antagonists on reperfusion arrhythmias in isolated rat hearts. Yasutake, M., Avkiran, M. Mol. Cell. Biochem. (1995) [Pubmed]
  15. Comparison of alpha 1-adrenergic receptor subtypes distinguished by chlorethylclonidine and WB 4101. Minneman, K.P., Han, C., Abel, P.W. Mol. Pharmacol. (1988) [Pubmed]
  16. Renal alpha 1-adrenergic receptor subtypes: MDCK-D1 cells, but not rat cortical membranes possess a single population of receptors. Klijn, K., Slivka, S.R., Bell, K., Insel, P.A. Mol. Pharmacol. (1991) [Pubmed]
  17. Permissive role of calcium in alpha 1-adrenergic stimulation of pineal phosphatidylinositol phosphodiesterase (phospholipase C) activity. Ho, A.K., Chik, C.L., Klein, D.C. J. Pineal Res. (1988) [Pubmed]
  18. Structure-activity relationships for prazosin and WB 4101 analogues as alpha 1-adrenoreceptor antagonists. Giardinà, D., Bertini, R., Brancia, E., Brasili, L., Melchiorre, C. J. Med. Chem. (1985) [Pubmed]
  19. Serotonergic control of phenylephrine-induced cyclic 3,5'-adenosine monophosphate and inositol phosphates formation in rat hippocampus. Consolo, S., Cicioni, P., Ladinsky, H., Rusconi, L., Parenti, M., Vinci, R. J. Pharmacol. Exp. Ther. (1988) [Pubmed]
  20. [3H]WB4101 labels the 5-HT1A serotonin receptor subtype in rat brain. Guanine nucleotide and divalent cation sensitivity. Norman, A.B., Battaglia, G., Creese, I. Mol. Pharmacol. (1985) [Pubmed]
  21. Structure-activity relationships in 1,4-benzodioxan-related compounds. 7. Selectivity of 4-phenylchroman analogues for alpha(1)-adrenoreceptor subtypes. Quaglia, W., Pigini, M., Piergentili, A., Giannella, M., Gentili, F., Marucci, G., Carrieri, A., Carotti, A., Poggesi, E., Leonardi, A., Melchiorre, C. J. Med. Chem. (2002) [Pubmed]
  22. Centrally acting hypotensive agents with affinity for 5-HT1A binding sites inhibit forskolin-stimulated adenylate cyclase activity in calf hippocampus. Schoeffter, P., Hoyer, D. Br. J. Pharmacol. (1988) [Pubmed]
  23. Differentiation of alpha 1-adrenergic receptors linked to phosphatidylinositol turnover and cyclic AMP accumulation in rat brain. Johnson, R.D., Minneman, K.P. Mol. Pharmacol. (1987) [Pubmed]
  24. Regional variations in alpha 1-adrenergic receptor subtypes in rat brain. Wilson, K.M., Minneman, K.P. J. Neurochem. (1989) [Pubmed]
  25. Regulation of ERK phosphorylation in differentiated arterial muscle of rabbits. Ratz, P.H. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  26. Pharmacological and immunocytochemical characterization of subtypes of alpha-1 adrenoceptors in dog aorta. Low, A.M., Lu-Chao, H., Wang, Y.F., Brown, R.D., Kwan, C.Y., Daniel, E.E. J. Pharmacol. Exp. Ther. (1998) [Pubmed]
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  28. The expression of alpha 1 adrenoceptor subtypes changes with age in the rat aorta. Gurdal, H., Tilakaratne, N., Brown, R.D., Fonseca, M., Friedman, E., Johnson, M.D. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  29. Differences between the alpha 2-adrenoceptor in rat submaxillary gland and the alpha 2A-and alpha 2B-adrenoceptor subtypes. Michel, A.D., Loury, D.N., Whiting, R.L. Br. J. Pharmacol. (1989) [Pubmed]
  30. Subtypes of alpha 1-adrenoceptors in hippocampus of pigs, guinea-pigs, calves and humans: regional differences. Hoyer, D., Jones, C.R., Ford, W., Palacios, J.M. Eur. J. Pharmacol. (1990) [Pubmed]
  31. Contribution of an alpha 1-adrenergic receptor subtype to the expression of the "ventral tegmental area syndrome". Trovero, F., Blanc, G., Hervé, D., Vézina, P., Glowinski, J., Tassin, J.P. Neuroscience (1992) [Pubmed]
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  34. Capillary electrophoretic and high-performance liquid chromatographic studies of the enantioselective separation of alpha1-adrenoreceptor antagonists. Andrisano, V., Gotti, R., Cavrini, V., Tumiatti, V., Felix, G., Wainer, I.W. Journal of chromatography. A. (1998) [Pubmed]
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