Pharmacological characterization of A-131701, a novel ?1-adrenoceptor antagonist selective for ?1A- and ?1D-compared to ?1B-adrenoceptors

Hancock, Arthur A.; Buckner, Steven A.; Brune, Michael E.; Katwala, Sweta P.; Milicic, Ivan; Ireland, Lynne M.; Morse, Patricia A.; Knepper, Sheila M.; Meyer, Michael D.; Chapple, Christopher R.; Chess-Williams, Russ; Noble, A J; Williams, Michael; Kerwin, James F.

doi:10.1002/(sici)1098-2299(199808)44:4<140::aid-ddr2>3.0.co;2-r

Cited by 14 publications

(26 citation statements)

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“…Radioligand binding assays were performed as described (Hancock et al, 1998b), by using recombinant human ␣ 1 -adrenoceptors expressed in mouse fibroblast cells (LTK Ϫ ). Membranes were prepared from confluent cells of stable single cell clones as previously described (Hancock et al, 1998b).…”

Section: Methodsmentioning

confidence: 99%

“…Fiduxosin was dissolved in 10% DMSO and all serial dilutions were performed manually because of the tendency of this compound to adhere to automated pipetting devices. Assays were terminated by filtration under vacuum through Whatman GF/B filters and data analyzed as previously described (Hancock et al, 1998b).…”

Section: Methodsmentioning

confidence: 99%

“…Rat vas deferens, spleen, or aorta or canine prostate glands (male beagles aged Ͼ3 years) were studied as previously described (Hancock et al, 1998b). For isolated rabbit urethra, female New Zealand White rabbits (1.75-3.5 kg) were sacrificed by means of a 0.5-ml/kg i.p.…”

Section: Methodsmentioning

confidence: 99%

“…The urethra was removed with the urinary bladder and immediately placed into Krebs-Henseleit buffer of the following composition: 119 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 2.5 mM CaCl 2 , 0.01 mM K 2 EDTA, 20 mM NaHCO 3 , 1.5 mM Mg 2 SO 4 , 11 mM dextrose, and 0.004 mM propranolol. The urethra was separated from the bladder, cut into four tissue rings approximately 3 to 4 mm in width, and subsequently fixed between a stationary glass rod and a force-displacement transducer as previously described for other isolated tissues (Hancock et al, 1998b) at a basal preload of 1.0 g. After equilibration with intermittent rinsing for 45 to 60 min, tissues were primed with 80 mM KCl, rinsed to basal tension and stimulated with 10 M phenylephrine (PE). After 60 min equilibration, a control (PE) cumulative concentration response was determined for each tissue.…”

Section: Methodsmentioning

confidence: 99%

“…After 60 min equilibration, a control (PE) cumulative concentration response was determined for each tissue. After a 75-min washout, agonist concentration-response curves were generated in the presence and absence of test compounds and the data analyzed as described previously (Hancock et al, 1998b). Fiduxosin was dissolved in 100% DMSO with subsequent dilution in DMSO.…”

Section: Methodsmentioning

confidence: 99%

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

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

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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...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Hancock

Buckner²,

Brune³

et al. 2002

J Pharmacol Exp Ther

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A revised conceptual framework for mouse vomeronasal pumping and stimulus sampling

Hamacher,

Degen,

Franke

et al. 2024

Current Biology

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Chapter 20. Toward the development of α1a adrenergic receptor antagonists

Bock¹,

Patane²

2000

Annual Reports in Medicinal Chemistry

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Pharmacological characterization of A-131701, a novel ?1-adrenoceptor antagonist selective for ?1A- and ?1D-compared to ?1B-adrenoceptors

Cited by 14 publications

References 46 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

A revised conceptual framework for mouse vomeronasal pumping and stimulus sampling

Chapter 20. Toward the development of α1a adrenergic receptor antagonists

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Pharmacological characterization of A-131701, a novel ?1-adrenoceptor antagonist selective for ?1A- and ?1D-compared to ?1B-adrenoceptors

Cited by 14 publications

References 46 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

A revised conceptual framework for mouse vomeronasal pumping and stimulus sampling

Chapter 20. Toward the development of α1a adrenergic receptor antagonists

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Product

Resources

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

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