AE9C90CB: a novel, bladder-selective muscarinic receptor antagonist for the treatment of overactive bladder.

Article Details

Citation

Sinha S, Gupta S, Malhotra S, Krishna NS, Meru AV, Babu V, Bansal V, Garg M, Kumar N, Chugh A, Ray A

AE9C90CB: a novel, bladder-selective muscarinic receptor antagonist for the treatment of overactive bladder.

Br J Pharmacol. 2010 Jul;160(5):1119-27. doi: 10.1111/j.1476-5381.2010.00752.x.

PubMed ID
20590605 [ View in PubMed
]
Abstract

BACKGROUND AND PURPOSE: AE9C90CB (N- [(1R, 5S, 6R)-3-azabicyclo [3.1.0] hex-6-ylmethyl]-2-hydroxy-N-methyl-2, 2-diphenylacetamide), a novel muscarinic receptor antagonist, was synthesized for the treatment of overactive bladder. Here we describe the in vitro and in vivo profiles of AE9C90CB for action in bladder over salivary gland and compare it with four agents already in clinical use (tolterodine, oxybutynin, solifenacin and darifenacin). EXPERIMENTAL APPROACH: Radioligand binding assay and isolated tissue-based functional assay were used to evaluate affinity, potency, and receptor subtype selectivity of compounds. Inhibition of carbachol-induced increase in intravesicular pressure and salivary secretion were measured in anaesthetized rabbits to assess the functional selectivity. KEY RESULTS: In vitro radioligand binding study using human recombinant muscarinic receptors showed that AE9C90CB had greater affinity for M(3) muscarinic receptors with pKi of 9.90 +/- 0.11 and was 20-fold more selective for M(3) than for M(2) muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pK(B), 9.13 +/- 0.12). In anaesthetized rabbits after intravenous administration, AE9C90CB dose dependently inhibited carbachol-induced increase in intravesicular pressure and salivary secretion, and exhibited functional selectivity for urinary bladder over salivary gland which was ninefold better than that of oxybutynin. CONCLUSIONS AND IMPLICATIONS: We have identified AE9C90CB, a compound exhibiting moderate selectivity for M(3) over M(2) receptors but greater selectivity for urinary bladder over salivary gland than oxybutynin, tolterodine, solifenacin and darifenacin. Therefore, AE9C90CB may be a promising compound for the treatment of overactive bladder with reduced potential to cause dry mouth than currently available antimuscarinic drugs.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
OxybutyninMuscarinic acetylcholine receptor M1ProteinHumans
Yes
Antagonist
Details
OxybutyninMuscarinic acetylcholine receptor M2ProteinHumans
Yes
Antagonist
Details
OxybutyninMuscarinic acetylcholine receptor M3ProteinHumans
Yes
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M1ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M2ProteinHumans
Unknown
Antagonist
Details
SolifenacinMuscarinic acetylcholine receptor M3ProteinHumans
Yes
Antagonist
Details