In vitroα1‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α1A‐adrenoceptor selective antagonists

Williams, Timothy J.; Blue, David R.; Daniels, Donald V.; Davis, Beverley J.; Elworthy, Todd R.; Gever, Joel R.; Kava, M. Shannon; Morgans, David J.; Padilla, Fernando; Tassa, S; Vimont, Rachel L.; Chapple, Christopher R.; Chess-Williams, Russ; Eglen, Richard M.; Clarke, David E.; Ford, Anthony

doi:10.1038/sj.bjp.0702541

Cited by 80 publications

(59 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This hypothesis was supported by results obtained in SHR, in which fiduxosin was less hypotensive than other agents on a mole per kilogram basis, and also elicited weaker, more transient effects in a postural hypotension challenge. Similar results have been reported with the ␣ 1a -selective compounds Ro-70-0004 (Williams et al, 1999), RWJ-38063, and RWJ-69736 (Pulito et al, 2000), supporting the importance of ␣ 1b -adrenoceptors for cardiovascular function as suggested by data with knockout mice lacking the ␣ 1b -adrenoceptor gene (Cavalli et al, 1997). Recently, a novel compound has been described, B8805-033 (Eltze et al, 2001), with chemical and pharmacological similarities to 5-methyl-urapidil and flesinoxan.…”

Section: Discussionsupporting

confidence: 75%

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Benign prostatic hyperplasia (BPH), common in aging males, is often treated with ␣ 1 -adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at ␣ 1A -and ␣ 1D -(compared with ␣ 1B -) adrenoceptors were evaluated that would block lower urinary tract ␣ 1 -adrenoceptors in preference to cardiovascular ␣ 1B -adrenoceptors. 9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydroABT-980) was tested in radioligand binding assays, isolated tissue bioassays, intraurethral pressure (IUP) tests in isoflurane-anesthetized dogs, and blood pressure analyses in spontaneously hypertensive rats (SHR). Fiduxosin had higher affinity for cloned human ␣ 1a -(0.16 nM) and ␣ 1d -adrenoceptors (0.92 nM) in radioligand binding studies compared with ␣ 1b -adrenoceptors (25 nM) or in isolated tissue bioassays [pA 2 values of 8.5-9.6 for ␣ 1A -receptors in rat vas deferens or canine prostate strips, 8.9 at ␣ 1D -adrenoceptors (rat aorta), compared with 7.1 at ␣ 1B -adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative ␣ 1L -adrenoceptors in the rabbit urethra (pA 2 value of 7.58). Fiduxosin blocked epinephrineinduced increases in canine IUP (pseudo-pA 2 value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC 0360 min) for the hypotensive response was dose related with a log index value for fiduxosin of 5.23, indicating a selectivity of 770-fold comparing IUP to MAP effects. Preferential antagonism of ␣ 1A -and ␣ 1D -versus ␣ 1B -adrenoceptors in vitro, blockade of putative ␣ 1L -sites in vitro, and selective effects on lower urinary tract function versus blood pressure in vivo by fiduxosin suggest the potential utility of this compound for the treatment of BPH.Benign prostatic hyperplasia (BPH), a change in the size, composition, and function of the prostate gland, leads to obstruction of the bladder and urethra in middle-aged and elderly males. The enlarged prostate is composed of glandular epithelium and a large stromal component containing mostly smooth muscle (Shapiro and Lepor, 1991). Although the term BPH might suggest that symptoms arise exclusively from increased organ size causing mechanical obstruction of urine flow, no correlation between prostate size and symptom severity has been shown (Shapiro and Lepor, 1995). Rather, an important "dynamic" component to BPH results from alterations in sympathetic control of prostatic smooth muscle tone, mediated primarily through ␣ 1 -adrenoceptor mecha- ; DMSO, dimethyl sulfoxide; PE, phenylephrine; IUP, intraurethral pressure; EPI, epinephrine; SHR, spontaneously hypertensive rats; MAP, mean arterial blood pressure; AUC, area under the curve; pED 50 , negative logarithm of the molar dose of compound required to elicit a reduction in blood pressure for 60 min to a point midway between hypertensive and normotensive; ANOVA, analysis of variance; K i , inhibition constant as a measure of drug affinity for a receptor, equivalent to the concentra...

show abstract

Section: Discussionsupporting

confidence: 75%

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…In the cavernous artery, pharmacological analysis of these antagonists was clearcut. RS 100329, selective for the a 1A -AR subtype (Williams et al, 1999), inhibited PE responses potently and competitively. The high potency and Schild compliance of RS 100329 indicated that there is no need to invoke participation from other a 1 -AR subtypes.…”

Section: Discussionmentioning

confidence: 97%

“…RS 100329 has been shown to be a potent antagonist at a 1A -ARs with a pA 2 /pK B of between 9.2 and 9.6 (Williams et al, 1999;Choppin et al, 2001;Cleary et al, 2003). Pre-incubation with 100 nM RS 100329 caused no further rightward movement of the PE response in dorsal arteries, and a pK B of 9.0370.07 (n ¼ 6) was determined from 1 and 10 nM antagonist data.…”

Section: Agonist Profilesmentioning

confidence: 97%

α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Morton

Daly

Jackson

et al. 2007

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: Maintained penile erection depends on the absence of a-adrenoceptor (a-AR) activation and so can be facilitated by a-blockers. This study seeks the a 1 -AR subtypes involved in order to inform the pro-erectile consequences of subtype selective blockade. Experimental approach: Wire myography was used with dorsal (nutritional supply) and cavernous (erectile inflow) penile arteries; standard a-AR-selective agonists and antagonists were employed to classify responses. Key results: In both penile arteries noradrenaline (NA) and phenylephrine (PE, a 1 -AR agonist) caused concentrationdependent contractions. Sensitivity to NA was increased by NA uptake blockers, cocaine (3 mM) and corticosterone (30 mM). PE responses were antagonised by phentolamine (non-selective a-AR: dorsal pK B 8.00, cavernous 8.33), prazosin (nonsubtype-selective a 1 -AR: dorsal 8.60, cavernous 8.41) and RS100329 (a 1A -AR selective: dorsal 9.03, cavernous 8.80) but not by BMY7378 (a 1D -AR selective: no effect at 1-100 nM) or Rec15/2615 (a 1B -AR selective: no effect at 1-100 nM). Schild analysis was straightforward in cavernous artery, indicating that PE activates only a 1A -AR. In dorsal artery Schild slopes were low, though a 1A -AR was still indicated. Analysis using UK 14,304 and rauwolscine indicated an a 2 -AR component in dorsal artery that may account for low slopes to a 1 -AR antagonists. Conclusions and implications: Penile arteries have a predominant, functional a 1A -AR population with little evidence of other a 1 -AR subtypes. Dorsal arteries (nutritional supply) also have a 2 -ARs. Thus, a-AR blockers with affinity for a 1A -AR or a 2 -AR would potentially have pro-erectile properties; the combination of these perhaps being most effective. This should inform the design of drugs to assist/avoid penile erection.

show abstract

“…and demonstrates a 126-and 50-fold selectivity over α 1B and α 1D -adrenoceptor subtypes, 19,20 thus at the concentration used in the present study (10nM) it would only have an action at α 1A -adrenoceptors. The lack of involvement of α 1D -adrenoceptors was confirmed using BMY7378, an antagonist with a greater than 100-fold high affinity for the α 1D -adrenoceptor subtype over α 1A and α 1B -adrenoceptors.…”

Section: α-Adrenoceptorsmentioning

confidence: 99%

Adrenoceptor Function and Expression in Bladder Urothelium and Lamina Propria

Moro

Tajouri

Chess-Williams

2013

Urology

View full text Add to dashboard Cite

In vitroα₁‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α_1A‐adrenoceptor selective antagonists

Cited by 80 publications

References 25 publications

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Adrenoceptor Function and Expression in Bladder Urothelium and Lamina Propria

Contact Info

Product

Resources

About

In vitroα1‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α1A‐adrenoceptor selective antagonists

Cited by 80 publications

References 25 publications

Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α1-Adrenoceptor Antagonist with Uroselective Properties

α1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries

Adrenoceptor Function and Expression in Bladder Urothelium and Lamina Propria

Contact Info

Product

Resources

About

In vitroα₁‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α_1A‐adrenoceptor selective antagonists

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

Preclinical Pharmacology of Fiduxosin, a Novel α₁-Adrenoceptor Antagonist with Uroselective Properties

α_1A‐Adrenoceptors mediate contractions to phenylephrine in rabbit penile arteries