Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.

Article Details

Citation

Maruyama S, Oki T, Otsuka A, Shinbo H, Ozono S, Kageyama S, Mikami Y, Araki I, Takeda M, Masuyama K, Yamada S

Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder.

J Urol. 2006 Jan;175(1):365-9.

PubMed ID
16406943 [ View in PubMed
]
Abstract

PURPOSE: We characterized the binding affinities of several antimuscarinic agents in human muscarinic receptors. MATERIALS AND 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.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
OxybutyninMuscarinic acetylcholine receptor M1ProteinHumans
Yes
Antagonist
Details
OxybutyninMuscarinic acetylcholine receptor M3ProteinHumans
Yes
Antagonist
Details
PropiverineMuscarinic acetylcholine receptor M1ProteinHumans
Yes
Antagonist
Details
PropiverineMuscarinic acetylcholine receptor M2ProteinHumans
Yes
Antagonist
Details
PropiverineMuscarinic acetylcholine receptor M3ProteinHumans
Yes
Antagonist
Details
PropiverineMuscarinic acetylcholine receptor M4ProteinHumans
Unknown
Antagonist
Details
PropiverineMuscarinic acetylcholine receptor M5ProteinHumans
Yes
Not AvailableDetails
PropiverineVoltage-dependent L-type calcium channel subunit alpha-1CProteinHumans
Yes
Antagonist
Details
TolterodineMuscarinic acetylcholine receptor M4ProteinHumans
Yes
Antagonist
Details
TolterodineMuscarinic acetylcholine receptor M5ProteinHumans
Yes
Antagonist
Details