title: Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.
abstract: OBJECTIVE
  We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors.
  
  
  METHODS
  Competitive inhibitory effects of antimuscarinic agents on specific NMS [H] (PerkinElmer Life Sciences, Boston, Massachusetts) binding were examined in human tissue homogenates and in CHO-K1 cell membranes expressing human muscarinic receptor subtypes.
  
  
  RESULTS
  Oxybutynin, propiverine, tolterodine, the respective metabolites DEOB, DPr-P-4(N-->O) and 5-HM, and darifenacin inhibited in concentration dependent fashion specific [(3)H]NMS binding in homogenates of the human bladder and parotid gland as well as in membranes of CHO-K1 cell lines expressing human muscarinic M(1) to M(5) receptor subtypes. Based on inhibition constant values the inhibitory effects of tolterodine, 5-HM and DPr-P-4(N-->O) were 1.4 to 1.7 times greater in the bladder than in the parotid gland, whereas the inhibitory effects of oxybutynin, DEOB, propiverine and darifenacin were 2 to 10 times greater in the parotid gland. Consequently tolterodine, 5-HM and DPr-P-4(N-->O) compared with oxybutynin, DEOB, propiverine and darifenacin were found to show 3 to 4 times greater affinity to muscarinic receptors in the human bladder than in the parotid gland. Tolterodine and 5-HM were 2-fold more potent for inhibiting specific [(3)H]NMS binding at cell membranes expressing the M(2) vs the M(3) subtype. Conversely oxybutynin, DEOB, propiverine, DPr-P-4(N-->O) and darifenacin showed 2 to 22 times higher affinity to the M(3) than to the M(2) subtype.
  
  
  CONCLUSIONS
  Compared with oxybutynin, tolterodine, 5-HM and DPr-P-4(N-->O) may bind more selectively to muscarinic receptors in the human bladder than in the parotid gland.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Maruyama
authors.forename: Tomomi
authors.initials: T
authors.lastname: Oki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shinbo
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Ozono
authors.forename: Shinji
authors.initials: S
authors.lastname: Kageyama
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Mikami
authors.forename: Isao
authors.initials: I
authors.lastname: Araki
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Masuyama
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D006801:Humans; D018727:Muscarinic Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D010306:Parotid Gland / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects*; D014549:Urinary Incontinence / Q000188:drug therapy*
chemical_list: D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic