Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.
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.
Maruyama
Shuji
S
Department of Pharmacokinetics and Pharmacodynamics and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Oki
Tomomi
T
Otsuka
Atsushi
A
Shinbo
Hitoshi
H
Ozono
Seiichiro
S
Kageyama
Shinji
S
Mikami
Yuuki
Y
Araki
Isao
I
Takeda
Masayuki
M
Masuyama
Keisuke
K
Yamada
Shizuo
S
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*
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic