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 M3 muscarinic receptors with pKi of 9.90 Ϯ 0.11 and was 20-fold more selective for M3 than for M2 muscarinic receptors. AE9C90CB exhibited an unsurmountable antagonism on rat bladder strips (pKB, 9.13 Ϯ 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 M3 over M2 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.
British Journal of Pharmacology
IntroductionOveractive bladder (OAB) is one of the most common causes of bladder control problems. It derives from the uncontrolled activity of the detrusor muscle during bladder filling, leading to the symptoms of urinary urgency and increased frequency of micturition with or without incontinence . Symptoms of OAB are highly prevalent in men and women of all ages, and the risk of developing this condition increases with age (Wein and Rovner, 1999), with a sharp increase among patients 40 years of age or older (Stewart et al., 2003). OAB is a disruptive condition that not only can cause embarrassment but also can have a significant impact on the patient's quality of life (Abrams et al., 2000;Bogner et al., 2002). Despite the disturbing nature of OAB, only 20% of patients are on medical treatments, and in addition, OAB is an under-diagnosed condition. Although not life-threatening, the quality of life of patients with OAB is poorer than that of diabetics (Liberman et al., 2001).Urinary bladder contraction is predominantly under the control of the parasympathetic system (de Groat et al., 1981), where the primary input is via the muscarinic cholinoce...