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Chemical Compound Review

Darfenacin     2-[1-[2-(2,3- dihydrobenzofuran-5...

Synonyms: darifenicin, SureCN113331, ANW-57645, CHEBI:431080, AC1L2HBG, ...
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Disease relevance of UK-88525

  • Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder [1].
  • Furthermore, high M(3) receptor occupation is the likely explanation for the greater propensity of darifenacin and oxybutynin to cause dry mouth and/or constipation [2].
  • The affinity of the M(3) selective antagonists darifenacin or p-fluoro-hexahydrosiladifenadol (p-F-HHSiD) was determined in six of the seven spinal injury patient specimens [3].

Psychiatry related information on UK-88525

  • RESULTS: For the primary end points of memory scanning sensitivity, speed of choice reaction time and word recognition sensitivity, there were no statistically significant differences for darifenacin vs placebo [4].
  • In this study we evaluated the effect of darifenacin, an M3 selective antagonist, on cognitive function in elderly volunteers without clinical dementia [4].

High impact information on UK-88525


Chemical compound and disease context of UK-88525


Biological context of UK-88525

  • Long-term (24-h) treatment of Chinese hamster ovary cells expressing the N410Y mutant M(2) mACh receptor with certain mACh receptor inverse agonists (atropine, darifenacin, and pirenzepine) elicited a concentration-dependent up-regulation of cell surface receptor expression [9].
  • Following alkylation of muscarinic M(3) receptors, darifenacin bound to a single low affinity site, indicating binding to muscarinic M(2) receptors [10].
  • The study was divided into two periods of 7 days of treatment with either darifenacin 5 mg t.d.s. or placebo with the patient crossing over to the alternative treatment after a washout period of 7 days [11].
  • The covariates race, gender and circadian rhythm accounted for only approximately half of the variability in the estimated exposures to darifenacin [12].
  • The data on UH-AH 37 and darifenacin support the view that a selectivity for muscarinic M3/m3 over M2/m2 receptors may result in a more pronounced effect on salivation than on bladder contraction [13].

Anatomical context of UK-88525


Associations of UK-88525 with other chemical compounds

  • Inhibition of PKC with chelerythrine increases darifenacin affinity, whereas inhibition of rho kinase, PKA, PKG, and protein kinase C (PKC) with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine.2HCl (H7) reduces the carbachol potency while increasing darifenacin affinity [18].
  • We investigated the functional antagonist potency of darifenacin, and the antimuscarinic drugs propiverine, oxybutynin and atropine, on human detrusor smooth muscle [19].
  • SUBJECTS AND METHODS: In this double-blind, four-way crossover study, 27 healthy men (aged 19-44 years) were randomized to receive darifenacin 7.5 mg or 15 mg once daily, dicyclomine 20 mg four times daily or matching placebo [20].

Gene context of UK-88525


Analytical, diagnostic and therapeutic context of UK-88525

  • With repeated once-daily oral administration of the PR formulation, peak plasma concentrations of darifenacin are achieved approximately 7 hours post-dose [1].
  • The system is described, linked to HPLC/APCI-MS/MS, for the determination of darifenacin in human plasma [24].
  • MATERIALS AND METHODS: This double-blind, 3-period crossover study randomized 129 volunteers 65 years or older with no/mild cognitive impairment to receive 3 of 5 treatments, namely darifenacin controlled release (3.75, 7.5 or 15 mg once daily), darifenacin immediate-release (5 mg 3 times daily) or matching placebo for 14 days [4].
  • MATERIALS AND METHODS: In this multicenter, double-blind study subjects with urinary urgency for 6 months or greater and episodes of urgency 4 times or greater daily were randomized to darifenacin controlled release tablets (30 mg once daily) or placebo [25].
  • AIM: To evaluate the efficacy, tolerability and safety of darifenacin, an M(3) selective receptor antagonist, in the subgroup of older patients from a pooled analysis of three phase III, multicentre, randomized, double-blind clinical trials in patients with overactive bladder (OAB) [26].


  1. The clinical pharmacokinetics of darifenacin. Skerjanec, A. Clinical pharmacokinetics. (2006) [Pubmed]
  2. Muscarinic receptors in the bladder: from basic research to therapeutics. Hegde, S.S. Br. J. Pharmacol. (2006) [Pubmed]
  3. The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Pontari, M.A., Braverman, A.S., Ruggieri, M.R. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2004) [Pubmed]
  4. Assessment of cognitive function of the elderly population: effects of darifenacin. Lipton, R.B., Kolodner, K., Wesnes, K. J. Urol. (2005) [Pubmed]
  5. Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder. Oki, T., Kageyama, A., Takagi, Y., Uchida, S., Yamada, S. J. Urol. (2007) [Pubmed]
  6. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Ohtake, A., Ukai, M., Hatanaka, T., Kobayashi, S., Ikeda, K., Sato, S., Miyata, K., Sasamata, M. Eur. J. Pharmacol. (2004) [Pubmed]
  7. Treatment of the overactive bladder syndrome with muscarinic receptor antagonists - a matter of metabolites? Michel, M.C., Hegde, S.S. Naunyn Schmiedebergs Arch. Pharmacol. (2006) [Pubmed]
  8. Preview of new drugs for overactive bladder and incontinence: darifenacin, solifenacin, trospium, and duloxetine. Kershen, R.T., Hsieh, M. Current urology reports. (2004) [Pubmed]
  9. Constitutive activity and inverse agonism at the M2 muscarinic acetylcholine receptor. Nelson, C.P., Nahorski, S.R., Challiss, R.A. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  10. Muscarinic receptor subtypes in the human colon: lack of evidence for atypical subtypes. Mansfield, K.J., Mitchelson, F.J., Moore, K.H., Burcher, E. Eur. J. Pharmacol. (2003) [Pubmed]
  11. Pharmacodynamics of anticholinergic agents measured by ambulatory urodynamic monitoring: a study of methodology. Rosario, D.J., Smith, D.J., Radley, S.C., Chapple, C.R. Neurourology and urodynamics. (1999) [Pubmed]
  12. Population pharmacokinetic modelling of darifenacin and its hydroxylated metabolite using pooled data, incorporating saturable first-pass metabolism, CYP2D6 genotype and formulation-dependent bioavailability. Kerbusch, T., Wählby, U., Milligan, P.A., Karlsson, M.O. British journal of clinical pharmacology. (2003) [Pubmed]
  13. Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists. Gillberg, P.G., Sundquist, S., Nilvebrant, L. Eur. J. Pharmacol. (1998) [Pubmed]
  14. Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland. Nelson, C.P., Gupta, P., Napier, C.M., Nahorski, S.R., Challiss, R.A. J. Pharmacol. Exp. Ther. (2004) [Pubmed]
  15. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: changes in ageing. Mansfield, K.J., Liu, L., Mitchelson, F.J., Moore, K.H., Millard, R.J., Burcher, E. Br. J. Pharmacol. (2005) [Pubmed]
  16. Molecular and pharmacological characterization of muscarinic receptor subtypes in a rat parotid gland cell line: comparison with native parotid gland. Bockman, C.S., Bradley, M.E., Dang, H.K., Zeng, W., Scofield, M.A., Dowd, F.J. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  17. M(3) receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Ikeda, K., Kobayashi, S., Suzuki, M., Miyata, K., Takeuchi, M., Yamada, T., Honda, K. Naunyn Schmiedebergs Arch. Pharmacol. (2002) [Pubmed]
  18. M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. II. Denervated rat bladder. Braverman, A.S., Doumanian, L.R., Ruggieri, M.R. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  19. Pharmacological effects of darifenacin on human isolated urinary bladder. Miyamae, K., Yoshida, M., Murakami, S., Iwashita, H., Ohtani, M., Masunaga, K., Ueda, S. Pharmacology (2003) [Pubmed]
  20. Pharmacodynamic effects of darifenacin, a muscarinic M selective receptor antagonist for the treatment of overactive bladder, in healthy volunteers. Kay, G.G., Wesnes, K.A. BJU international. (2005) [Pubmed]
  21. A pooled analysis of three phase III studies to investigate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. Chapple, C., Steers, W., Norton, P., Millard, R., Kralidis, G., Glavind, K., Abrams, P. BJU international. (2005) [Pubmed]
  22. Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo. Kobayashi, S., Ikeda, K., Suzuki, M., Yamada, T., Miyata, K. Jpn. J. Pharmacol. (2001) [Pubmed]
  23. Darifenacin in the treatment of overactive bladder. Parsons, M., Robinson, D., Cardozo, L. International journal of clinical practice. (2005) [Pubmed]
  24. Rapid, solid phase extraction technique for the high-throughput assay of darifenacin in human plasma. Kaye, B., Herron, W.J., Macrae, P.V., Robinson, S., Stopher, D.A., Venn, R.F., Wild, W. Anal. Chem. (1996) [Pubmed]
  25. Increased warning time with darifenacin: a new concept in the management of urinary urgency. Cardozo, L., Dixon, A. J. Urol. (2005) [Pubmed]
  26. Treatment of overactive bladder in the older patient: pooled analysis of three phase III studies of darifenacin, an M3 selective receptor antagonist. Foote, J., Glavind, K., Kralidis, G., Wyndaele, J.J. Eur. Urol. (2005) [Pubmed]
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