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


METHODS
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.


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
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.
Sinha
S
S
Department of Pharmacology, Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India.
Gupta
S
S
Malhotra
S
S
Krishna
N S
NS
Meru
A V
AV
Babu
V
V
Bansal
V
V
Garg
M
M
Kumar
N
N
Chugh
A
A
Ray
A
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D002217:Carbachol / Q000037:antagonists & inhibitors; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D012469:Salivary Glands / Q000187:drug effects*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
C552599:AE9C90CB; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018727:Muscarinic Antagonists; D002217:Carbachol