Phenotype pharmacology of lower urinary tract α₁-adrenoceptors

Abstract

α₁-Adrenoceptors are involved in numerous physiological functions, including micturition. However, the pharmacological profile of the α₁-adrenoceptor subtypes remains controversial. Here, we review the literature regarding α₁-adrenoceptors in the lower urinary tract from the standpoint of α_1L phenotype pharmacology. Among three α₁-adrenoceptor subtypes (α_1A, α_1B and α_1D), α_1a-adrenoceptor mRNA is the most abundantly transcribed in the prostate, urethra and bladder neck of many species, including humans. In prostate homogenates or membrane preparations, α_1A-adrenoceptors with high affinity for prazosin have been detected as radioligand binding sites. Functional α₁-adrenoceptors in the prostate, urethra and bladder neck have low affinity for prazosin, suggesting the presence of an atypical α₁-adrenoceptor phenotype (designated as α_1L). The α_1L-adrenoceptor occurs as a distinct binding entity from the α_1A-adrenoceptor in intact segments of variety of tissues including prostate. Both the α_1L- and α_1A-adrenoceptors are specifically absent from Adra1A (α_1a) gene-knockout mice. Transfection of α_1a-adrenoceptor cDNA predominantly expresses α_1A-phenotype in several cultured cell lines. However, in CHO cells, such transfection expresses α_1L- and α_1A-phenotypes. Under intact cell conditions, the α_1L-phenotype is predominant when co-expressed with the receptor interacting protein, CRELD1α. In summary, recent pharmacological studies reveal that two distinct α₁-adrenoceptor phenotypes (α_1A and α_1L) originate from a single Adra1A (α_1a-adrenoceptor) gene, but adrenergic contractions in the lower urinary tract are predominantly mediated via the α_1L-adrenoceptor. From the standpoint of phenotype pharmacology, it is likely that phenotype-based subtypes such as the α_1L-adrenoceptor will become new targets for drug development and pharmacotherapy.

LINKED ARTICLE

This article is commented on by Ventura, pp. 1223–1225 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01663.x

Introduction

The lower urinary tract is responsible for urine storage and voiding (Andersson and Wein, 2004). In mammalian species including humans, the bladder detrusor muscle contracts through a parasympathetic cholinergic mechanism during micturition (Abrams et al., 2006; Wess et al., 2007). Besides the importance of the cholinergic system as the major mechanism for bladder neck muscle tone control, the adrenergic systems play significant roles in the regulation of bladder neck tone (Fig. 1). During the storage phase, the urethra and outlet region of the bladder is contracted to maintain continence. There is good pharmacological evidence supporting the view that noradrenaline-mediated contraction of the urethral smooth muscle has an important role (Andersson and Wein, 2004).

Figure 1.

Autonomic innervation and main functional receptors involved in controlling smooth muscle tension in lower urinary tract tissues. NA, noradrenaline; α_1L, α_1L-adrenoceptor; β₃, β₃-adrenoceptor; M₃, M₃-muscarinic acetylcholine receptor.

Among impairments in urine storage, stress urinary incontinence (SUI) is recognized as one of the most frequently occurring conditions. Deficient urethral or bladder neck closure may result in this condition. However, drug treatments for SUI are scarce, at present (Andersson and Wein, 2004). The density of noradrenergic nerves increases markedly towards the bladder neck and urethra (Gosling et al., 1999). α₁-Adrenoceptors play important roles in both urethral and bladder neck contraction, and may be related to SUI (Andersson and Wein, 2004).

During the voiding phase, prostatic smooth muscle tone contributes to outlet resistance regulation. Benign prostatic hyperplasia (BPH) is a common enlargement of the prostate gland that may lead to bladder outlet obstruction, and lower urinary tract symptoms. BPH is currently recognized as a target for pharmacotherapy utilizing α₁-adrenoceptor antagonists. In BPH patients, enlargement of the prostate increases bladder outlet resistance and thereby impedes physiological voiding. α₁-Adrenoceptor antagonists are believed to inhibit contraction of the prostate and urethra, and as a result, α₁-adrenoceptor antagonists such as tamsulosin, alfuzosin and silodosin effectively reduce resistance to urinary flow and are now clinically used in BPH patients (Lefevre-Borg et al., 1993; Cooper et al., 1999; Ruffolo and Hieble, 1999; Takeda et al., 1999; Chapple, 2001; Andersson, 2002; Michel and Vrydag, 2006).

The functional roles of α₁-adrenoceptors have been highlighted through the study of their roles in lower urinary tract physiology. These are supported by numerous studies including quantification of mRNAs, anatomical localization of mRNAs, or of receptors demonstrated by ligand-binding studies (Table 1). On the other hand, functional studies have shown discrepancies between the native α₁-adrenoceptors found in the lower urinary tract (so-called α_1L-adrenoceptor) and the classical α₁-adrenoceptors (α_1A, α_1B and α_1D; receptor nomenclature follows Alexander et al., 2011) (Table 2). Subsequent studies revealed the origin of these unique α₁-adrenoceptors in the lower urinary tract (Ford et al., 1997; Gray et al., 2008; Muramatsu et al., 2008; Nishimune et al., 2010b). In this review, we will introduce recent progress in the study of α₁-adrenoceptors in the lower urinary tract as an example of the importance of phenotype pharmacology (Kenakin, 2003; Muramatsu et al., 2005; 2008; Nelson and Challiss, 2007; Su et al., 2008).

Table 1.

α₁Adrenoceptor subtypes in lower urinary tract

Table 2.

α₁-Adrenoceptor subtypes and their pharmacological characterization

Gene	Receptor polypeptide	Phenotype	Affinity (mean pKB) Prazosin	Silodosin	Tamsulosin	RS-17053
ADRA1A	α1a	α1A	9.6	9.8	10.0	8.7
		α1L	8.0	9.8	10.0	6.3
ADRA1B	α1b	α1B	10.2	8.0	9.3	7.8
ADRA1D	α1d	α1D	10.0	8.4	9.9	7.8

Affinity values are from Morishima et al. (2007).

α₁-Adrenoceptor mRNAs in the lower urinary tract

Three cDNAs for distinct α₁-adrenoceptor subtypes (α_1a, α_1b and α_1d) have been cloned, and their pharmacological phenotypes are consistent with pharmacological characteristics of α₁-adrenoceptors found in many native tissues (Lomasney et al., 1991; Hieble et al., 1995) (Table 2). In the lower urinary tract, the mRNA and protein for these three subtypes have been demonstrated (Table 1) (Michelotti et al., 2000; Michel and Vrydag, 2006; Nishimune et al., 2010a). Among them, the α_1a-adrenoceptor mRNA is the most form in the lower urinary tract of many species (Table 1). Data from human studies indicate that the relative abundance ratio of α_1a- : α_1b- : α_1d-adrenoceptor mRNA is approximately 70:0:30 in the prostate and 90∼100:0:0∼10 in the urethra (Price et al., 1993; Faure et al., 1994; Nasu et al., 1996; 1998; Michel and Vrydag, 2006). Interestingly, however, the α_1a-adrenoceptor mRNA detected at the tissue level disappears in cultures of human prostatic smooth muscle cells, in contrast to the consistent expression of α_1b- and α_1d-adrenoceptor mRNAs (Boesch et al., 1999). The relative expression of α_1a-adrenoceptor mRNA in the lower urinary tract of humans has also been examined by in situ hybridization studies. In the human prostate, α_1a-adrenoceptor mRNA was mainly detected in the stroma, including smooth muscle cells, but not in the glandular epithelium (Walden et al., 1999).

Data regarding the expression of α₁-adrenoceptor mRNA in the human bladder are inconsistent, but it appears that the expression of α₁-adrenoceptor mRNA is extremely low in the bladder (Malloy et al., 1998; Nomiya and Yamaguchi, 2003). In the human detrusor, β (mainly β₃)-adrenoceptors are dominant over α-adrenoceptors, based on the fact that the normal response to noradrenaline is relaxation rather than contraction (Andersson, 1993). Therefore, we can conclude that the functional significance of α-adrenoceptors in the detrusor contraction may be marginal or non-existent (Fig. 1). On the other hand, the density of noradrenergic nerves increases markedly towards the bladder neck, where the smooth muscle receives a dense noradrenergic nerve supply (Gosling et al., 1999). In the human bladder, the predominant expression of α_1a-adrenoceptor mRNA in the dome, trigone and base has also been reported (Walden et al., 1997).

Thus, the mRNA data in human urinary tract indicate that the α_1a-adrenoceptor polypeptide is a potential target for pharmacotherapy in patients with BPH and SUI.

α₁-Adrenoceptor pharmacological anomalies in the lower urinary tract

The classical α₁-adrenoceptors (α_1A, α_1B and α_1D) show high affinity for prazosin (pKi or pK_B > 9) in most binding and functional studies (Lomasney et al., 1991; Hieble et al., 1995; Ford et al., 1996; Theroux et al., 1996; Taniguchi et al., 1999; Suzuki et al., 2000; Israilova et al., 2004) (Table 2). However, the functional α₁-adrenoceptors identified in the lower urinary tract are known to be relatively resistant to prazosin (Muramatsu et al., 2009) (pK_B=∼8) (Table 1). Thus, this pharmacological anomaly, despite the predominance of α_1a-adrenoceptor mRNA, caused confusion about the α₁-adrenoceptor subtypes in the lower urinary tract. Because different affinities for antagonists have traditionally been regarded as characteristic pharmacological criteria for defining novel receptors (Kenakin, 1995; Rang, 2006), the anomalous α₁-adrenoceptor showing low affinity for prazosin suggests the existence of a distinctive subtype (or phenotype).

Pharmacological heterogeneity of α₁-adrenoceptors was originally reported by Drew (1985), who first noted a wide variation in the functional affinities for yohimbine and prazosin. This evidence was confirmed in experiments with isolated blood vessels by Flavahan and Vanhoutte (1986), and they proposed two distinct α₁-adrenoceptor subtypes that could be distinguished by their different affinities for both prazosin and yohimbine (α_1H and α_1L according to their High or Low affinity for prazosin). This subclassification was subsequently extended by many pharmacologists and in many tissues including the lower urinary tract (Muramatsu et al., 1990; 1991; 1995; Ford et al., 1996; Testa et al., 1997; Stam et al., 1999; Argyle and McGrath, 2000). In this subclassification, the classical α_1A-, α_1B- and α_1D-adrenoceptors are included in the α_1H group, and the anomalous α₁-adrenoceptor showing low affinity for prazosin in the lower urinary tract has been reported as the α_1L-adrenoceptor (Muramatsu et al., 1991; 1995; Ford et al., 1996; Langer, 1999; Nishimune et al., 2010a). Antagonistic potencies against noradrenaline-induced contractions in rat, rabbit and human prostate are low for prazosin (pK_B=∼8) and α_1A-antagonists (5-methylurapidil, WB4101, RS-17053), but are high for silodosin and tamsulosin (Hiraoka et al., 1995; 1999; Ford et al., 1996; Leonardi et al., 1997; Testa et al., 1997; Van der Graaf et al., 1997; Morishima et al., 2007; Su et al., 2008). In contrast to this nomenclature, α₁-adrenoceptors in the lower urinary tract have been also named as α_1A-adrenoceptors in many reports (Table 1). Therefore, there has been confusion in defining the functional α₁-adrenoceptor in the lower urinary tract (Table 1), which may in part depend on distinct subclassifications (α_1H, α_1L vs. α_1A, α_1B, α_1D).

α₂-Adrenoceptor can also be detected at the mRNA and protein levels in urogenital tissues (Yablonsky et al., 1986; Michel and Vrydag, 2006). Therefore, the anomalous characteristics of adrenergic contractions in the lower urinary tract may be associated with the α₂-adrenoceptor. In fact, clonidine (α₂-agonist) can produce a significant contraction in the female rabbit urethra (Larsson et al., 1986). However, clonidine is inactive in the isolated female human urethra, while noradrenaline produces contractions through sites with low affinity for prazosin (Taki et al., 1999). These results show that the α₂-adrenoceptor is not significantly involved in the anomalous contraction in the human urethra (Ruffolo and Hieble, 1999), although there may be relevant species differences in this adrenoceptor.

Identification of α₁-adrenoceptors by radioligand binding assay

Because reliable subtype-specific α_1a-adrenoceptor antibodies were recently reported to be unavailable (Jensen et al., 2009), investigation of α₁-adrenoceptors at the protein level are herein summarized from radioligand-binding experiments.

Binding assay with membrane homogenates

Specific binding of [³H]-prazosin, [¹²⁵I]-HEAT, [³H]-tamsulosin and [³H]-silodosin to α₁-adrenoceptors in membrane preparations of the lower urinary tract has been detected, with the density of binding in the order, prostate > urethra > bladder. In the rat, rabbit and human prostate, the most abundant α₁-adrenoceptor is the α_1A-subtype, which has been identified as having high affinity for prazosin, tamsulosin, silodosin and other α_1A-selective antagonists (5-methylurapidil and RS-17053) (Tables 1 and 2). Thus, low-affinity sites for prazosin (α_1L-adrenoceptors) are not detected in the membrane preparations of lower urinary tract tissues and at subnanomolar concentrations of [³H]-prazosin. The high abundance of the binding sites showing α_1A-adrenoceptor profile in the lower urinary tract is in agreement with the mRNA expression data mentioned above.

Three α₁-adrenoceptor cDNAs (including splice variants of α_1A-adrenoceptors) were transfected in several cell lines (CHO cells, COS-7 cells, HEK293 cells, HeLa cells) and the pharmacological binding characteristics in the membrane preparations were compared with those in native tissues. The three recombinant α₁-adrenoceptors showed high (subnanomolar) affinity for prazosin (Table 2). The cloned α_1a-adrenoceptor and its splice variants showed the same pharmacological profile as that recognized in the membrane preparations of lower urinary tract (Lomasney et al., 1991; Theroux et al., 1996; Piao et al., 2000; Suzuki et al., 2000; Ramsay et al., 2004).

Binding assay with whole cells and intact tissues

Most radioligand-binding studies conducted to date have involved homogenates or membrane preparations of tissues or cells as a source of receptors. Because tissue/cell homogenization physically disturbs the receptor micro-environment, it may cause changes in some of the pharmacological characteristics of the receptor. Therefore, in order to retain the natural/native receptor conformation by minimizing physical agitation, whole cells or intact tissue segments must be used in binding assays.

Ford and co-workers reported that the pharmacological characteristics of the recombinant α_1a-adrenoceptor can vary substantially depending upon assay conditions (Ford et al., 1997; Daniels et al., 1999). In CHO cells expressing the recombinant α_1a-adrenoceptor, prazosin and RS-17053 (α_1A-selective antagonist) show substantially lower potency against functional responses (phosphatidyl inositol turnover and calcium influx) in intact cells than inhibition of radioligand binding to α_1a-adrenoceptors in membrane homogenates. Furthermore, the K_i values for prazosin and RS-17053 as competitive inhibitors of [³H]-prazosin binding to α_1a-adrenoceptors in these CHO cells are dependent on assay conditions, with lower affinity observed when binding is conducted under more physiological conditions (culture medium, intact cells, 37°C) than under conditions commonly employed for radioligand binding assays (artificial buffer, membrane homogenates, 20°C). These observations have led to the proposal that the α_1L-adrenoceptor may not represent an independent molecular entity, but rather may be an ‘affinity state’ of the α_1A-adrenoceptor that is predominant in lower urinary tract.

Recently, a tissue segment binding method was developed and applied to numerous tissues (Tanaka et al., 2004; Muramatsu et al., 2005). In this method, tissue segments are incubated (without homogenization) in a nutrient medium such as Krebs solution during the course of ligand binding. To identify the α₁-adrenoceptors having low affinity for prazosin, [³H]-silodosin was used instead of [³H]-prazosin, because [³H]-prazosin at subnanomolar concentrations cannot bind sufficiently to α_1L-adrenoceptors (Su et al., 2008; Muramatsu et al., 2009). Silodosin and its tritiated radioligand are known to be of equally high affinity for both the α_1A- and α_1L-adrenoceptors (Murata et al., 1999; Su et al., 2008) (Table 2).

In segments of human, mouse and rabbit prostate, the binding of [³H]-silodosin was biphasically displaced by prazosin, indicating the coexistence of high and low-affinity sites for prazosin, which correspond to α_1A- and α_1L-adrenoceptors (Morishima et al., 2007; Muramatsu et al., 2008; Su et al., 2008). This result is very different from the results obtained in homogenates, in which a single high-affinity site for prazosin (α_1A-adrenoceptor) was detected. The low-affinity site for prazosin in the prostate segments also showed low affinity for some α_1A-selective antagonists (RS-17053, 5-methylurapidil), but tamsulosin (which has high affinity for α_1A-, α_1L- and α_1D-subtypes) did not discriminate either the high- or low-affinity sites for prazosin. Similar results were obtained in studies of other tissues in which the α_1L-adrenoceptor was identified as a functional receptor (Hiraizumi-Hiraoka et al., 2004; Morishima et al., 2008; Muramatsu et al., 2008; 2009). From these observations, it was suggested that α_1L-adrenoceptors (or α_1L-phenotype) coexist with α_1A-adrenoceptors (or α_1A-phenotype) as pharmacologically distinct entities under intact segment conditions, whereas the pharmacological profile of α_1L-adrenoceptors converts to the α_1A-phenotype upon homogenization.

More recently, this conclusion was again confirmed in a recombinant system (Nishimune et al., 2010b). In the CHO cell line, transfection of α_1a-adrenoceptor cDNA predominantly expresses α_1A-adrenoceptor phenotype, with an extremely minor proportion of α_1L-adrenoceptor (less than 10% of total α₁-adrenoceptor). However, persistent over-expression of the protein, cysteine-rich epidermal growth factor-like domain 1α (CRELD1α), which was found as a potential α_1a-adrenoceptor-interacting protein candidate) strongly reduced the population of α_1A-adrenoceptor phenotype in CHO cells (Nishimune et al., 2010b). Although mechanisms underlying the interactions between generation of CRELD1α and α_1A-adrenoceptors and α_1L-adrenoceptors remain unclear, two distinct (α_1L-adrenoceptor-dominant and α_1A-adrenoceptor-dominant) CHO cell lines were eventually established. Under whole-cell conditions, in contrast to the α_1A-adrenoceptor, pharmacological and functional properties of the established α_1L-adrenoceptor show low affinity for prazosin and other α_1A-adrenoceptor antagonists (5-methylurapidil, RS-17053), and the agonist and antagonist pharmacology is consistent with the profile of the α_1L-adrenoceptor identified in the lower urinary tract. Therefore, from these lines of evidence, it may be now concluded that the α_1L-adrenoceptor is one of the α_1a-adrenoceptor gene products and occurs as an entity distinct from the α_1A-adrenoceptor phenotype under conditions when the tissue/cell is kept intact. This conclusion would also explain why α_1L-adrenoceptors could not be detected after homogenization but are easily recognized in functional bioassay studies with intact tissue strips (Muramatsu et al., 2009).

Identification of the gene encoding α_1L-adrenoceptor

Despite extensive searches at early stages after the proposal of the α_1L-adrenoceptor and the subsequent completion of the human genome sequencing project, a distinct gene for the proposed α_1L-adrenoceptor has not been identified. Rather, as described above, a close relationship between α_1L-adrenoceptor and α_1A-adrenoceptor has been considered (Ford et al., 1997; Hiraizumi-Hiraoka et al., 2004; Morishima et al., 2008).

In order to explore this possible link between α_1A- and α_1L-adrenoceptors, we analysed in vivo phenotypes of mice having disrupted alleles of the classical α₁-adrenoceptors (α_1A, α_1B and α_1D) (Muramatsu et al., 2008). The integrity of the α_1L-adrenoceptors were confirmed both in terms of ligand binding properties and contractile function in the Adra1B^−/− (α_1b^−/−) and Adra1D^−/− (α_1d^−/−) mice as well as in the wild-type mice. In contrast, both α_1L- and α_1A-adrenoceptors were completely absent from the Adra1A^−/− (α_1a^−/−) mice. These results unequivocally demonstrate that both α_1A-adrenoceptors and α_1L-adrenoceptors are derived from the same Adra1A (α_1a) gene (Gray et al., 2008; Muramatsu et al., 2008) (Table 2).

Observation of α_1L-adrenoceptor distribution by fluorescent probe

Alexa Fluor 488 dye conjugated with silodosin (Alexa-488-silodosin) was recently introduced as a fluorescent probe (Morishima et al., 2010). Alexa-488-silodosin retains the high affinity and selectivity for α_1A- and α_1L-adrenoceptors as shown by unlabelled silodosin. Histochemical experiments with this fluorescent probe clearly showed that Alexa-488-silodosin binds to the smooth muscle but not the glandular tissue in the human prostate, and that the binding is resistant to low concentrations of prazosin. These results are in good agreement with in situ hybridization data showing selective expression of α_1A-adrenoceptor mRNA in the stroma of the human prostate (Walden et al., 1999). As the Alexa-488-silodosin can specifically label α_1L-adrenoceptors, particularly by co-incubation with low concentrations of prazosin (to mask the α_1A-adrenoceptor), this novel molecular probe provides a versatile tool to study α_1L-adrenoceptor histochemically (Morishima et al., 2010).

Perspective

As mentioned above, recent progress in this field clearly demonstrates that two distinct α₁-adrenoceptor phenotypes (α_1A and α_1L) originate from a single α_1a-adrenoceptor gene and coexist in some tissues. However, adrenergic contraction in the lower urinary tract is predominantly mediated through α_1L-, but not α_1A-adrenoceptors (Fig. 1). In general, the affinity values (pKi or pK_B) for prazosin for α_1L-adrenoceptors are around 8, but recent studies reveal a further variation in prazosin affinity (pKi or pK_B= 6.3–8.5) at various α_1L-adrenoceptors in many tissues and species (Muramatsu et al., 2009). This is reminiscent of the original question on α₁-adrenoceptors (Drew, 1985), suggesting further heterogeneity in α_1L-adrenoceptor pharmacology. At present, the mechanisms underlying the expression of α_1L-adrenoceptor phenotype and its functional predominance in several tissues remain unknown. However, it is likely that the expression of divergent α_1L-adrenoceptor phenotypes is strongly dependent on any modification of the tissues of various species, rather than a simple variation of the α_1a-adrenoceptor protein or additional subtypes (Muramatsu et al., 2009; Nishimune et al., 2010a).

Recently, ample evidence has been accumulating suggesting that antagonist affinity is not necessarily constant at a given receptor expressed in different tissues/cells and examined under different assay conditions (Kenakin, 2003; Baker and Hill, 2007; Nelson and Challiss, 2007; Muramatsu et al., 2008). The α_1L-adrenoceptor exemplifies this type of variable affinity, as after homogenization, the phenotype changed from α_1L into α_1A. It is likely that tissue integrity is an important factor to determine receptor properties (Su et al., 2008; Muramatsu et al., 2009). Therefore, we may have to re-evaluate pharmacodynamic and pharmacokinetic effects of currently used drugs, and to reconstruct drug development strategies. Now, α₁-antagonists, such as tamsulosin, silodosin, alfuzosin, are clinically used in BPH patients. According to the evidence mentioned above, these antagonists appear to act mainly on functional α_1L-adrenoceptors in the lower urinary tract, but are not specific for the α_1L-adrenoceptor. The α_1L-adrenoceptors in the female urethra may be a new target in therapy for SUI. For this purpose, two α₁-adrenoceptor agonists (NS-49 and Ro 115-1240) have been developed. However, these compounds are full agonists of the α_1A-adrenoceptor or partial agonists of the α_1A/L-adrenoceptor (Obika et al., 1995; Blue et al., 2004; Musselman et al., 2004). Thus, more selective or specific drugs against α_1L-adrenoceptors may lead to improved uroselectivity.

Conclusion

Since the successful cloning of most receptors, it has become possible to elucidate numerous physiological responses by genome-based subtype (genotypes). However, there are still some unique phenotypes showing distinct pharmacology in native tissues. The α_1L-adrenoceptor is representative of this group, and originates from the α_1a-adrenoceptor gene together with the α_1A-adrenoceptor phenotype. In this review, we propose that different phenotypes are expressed from a single gene in native tissues (‘one gene-multiple phenotypes theory’), which may explain the long controversy regarding some putative receptors, such as α_1L-adrenoceptor in the lower urinary tract, and further highlights phenotype-dependent pharmacology (‘phenotype pharmacology’).

Glossary

BPH

benign prostatic hyperplasia

CRELD1α

cycteine-rich epidermal growth factor-like domain 1α

NS-49

(R)-(-)-3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulphonanilide hydrochloride

Ro

115-1240 (Dabuzalgron, R-450), N-[6-chloro-3-(4,5-dihydro-1H-imidazol-2-ylmethoxy)-2-methylphenyl] methanesulphonamide

RS-17053

N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-α, α-dimethyl-1 H-indole-3-ethanamine hydrochloride

silodosin

1-(3-hydroxypropyl)-5-[(2R)-({2-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino) propyl] indoline-7-carboxamide

SUI

stress urinary incontinence

WB4101

2(N[2,6-dimethyoxyphenoxyethyl])amino-methyl-1,4-benzodioxane

Conflict of interest

The authors declare no competing financial interests.