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

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 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...

In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats

“…Although the reason for this discrepancy is unclear, the effective dose levels and shapes of dose-response curves of antimuscarinics on increasing bladder capacity may depend on experimental conditions used. Furthermore, when we compared our present data with the available animal data, we found no large differences in the effective dose levels of individual antimuscarinics in terms of CCh-induced salivation and CCh-induced bradycardia (Ikeda et al 2002;Ohtake et al 2006;Sinha et al 2010). Thus, the present experimental system was considered appropriate to evaluate bladder selectivity.…”

“…Based on this concept, the inhibitory effect of antimuscarinics on detrusor contraction has been used conventionally as an effectiveness index in assessing their bladder selectivity in various animals (Kobayashi et al 2007b;McNamara et al 2009;Ohtake et al 2004Ohtake et al , 2006Sinha et al 2010). However, antimuscarinics at their therapeutic doses have been revealed to increase bladder capacity without inhibiting detrusor contractility in OAB patients, suggesting that antimuscarinics primarily act on the bladder afferent pathway during storage phase, thereby increasing bladder capacity and improving OAB symptoms (Andersson and Yoshida 2003;Finney et al 2006;Yamaguchi 2010).…”

Comparative Analysis of the Effects of Antimuscarinic Agents on Bladder Functions in Both Nonhuman Primates and Rodents

“…Although all three antimuscarinics are known to highly bind to plasma proteins (96 -99%) in humans (Abrams et al, 2006;Hegde, 2006) and circulating free drug levels are generally used to interpret target receptor occupancy, the plasma protein binding of each compound may vary between species. In addition, there may be species differences in the muscarinic receptor antagonistic activity of the drugs, although these differences are expected to be marginal based on previous reports (Ohtake et al, 2007;Sinha et al, 2010). Despite these caveats, as well as existence of active metabolites for tolterodine and oxybutynin in clinical use, if the plasma levels of antimuscarinics in rhesus monkeys are compared with those clinically used to treat OAB, the therapeutic plasma levels of tolterodine (approximately 10 nM), darifenacin (9 nM), and oxybutynin (2 nM) are overall lower than those needed to significantly increase bladder capacity in rhesus monkeys (Abrams et al, 2006;Hegde, 2006).…”

The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance & cognitive function

“…Delivery of drugs to the CNS depends on molecular characteristics; these include molecular size, polarity and lipophilicity (Table S3) . The physicochemical properties of oxybutynin and hyoscine hydrobromide grant these molecules high propensity to penetrate the blood–brain barrier freely, thus high concentrations can reach the central M1 receptors .…”