Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.

Article Details

Citation

Mansfield KJ, Chandran JJ, Vaux KJ, Millard RJ, Christopoulos A, Mitchelson FJ, Burcher E

Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.

J Pharmacol Exp Ther. 2009 Mar;328(3):893-9. doi: 10.1124/jpet.108.145508. Epub 2008 Nov 24.

PubMed ID
19029429 [ View in PubMed
]
Abstract

Recent studies have described muscarinic receptors on the mucosa and the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine, and trospium. Specimens were collected from asymptomatic patients (50-72 years old) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in Chinese hamster ovary cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low-affinity sites in mucosa and 78% low-affinity sites in detrusor, probably representing M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
FesoterodineMuscarinic acetylcholine receptor M2ProteinHumans
Unknown
Antagonist
Details
FesoterodineMuscarinic acetylcholine receptor M4ProteinHumans
Unknown
Antagonist
Details
FesoterodineMuscarinic acetylcholine receptor M5ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M1ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M2ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M3ProteinHumans
Yes
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M4ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M5ProteinHumans
Unknown
Antagonist
Details