Effect of Fiduxosin, an Antagonist Selective for α1A- and α1D-Adrenoceptors, on Intraurethral and Arterial Pressure Responses in Conscious Dogs
- Michael E. Brune,
- Sweta P. Katwala,
- Ivan Milicic,
- David G. Witte,
- James F. Kerwin, Jr.,
- Michael D. Meyer,
- Arthur A. Hancock and
- Michael Williams
- Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois
- Michael E. Brune, 047C AP9, Abbott Laboratories,100 Abbott Park Rd., Abbott Park, IL 60064-6118. E-mail: michael.e.brune{at}abbott.com
Abstract
Fiduxosin is an α1-adrenoceptor antagonist with higher affinity for α1A-adrenoceptors and for α1D-adrenoceptors than for α1B-adrenoceptors. Our hypothesis is that such a compound with higher affinity for subtypes implicated in the control of lower urinary tract function and lower affinity for a subtype implicated in the control of arterial pressure could result in a superior clinical profile for the treatment of lower urinary tract symptoms suggestive of benign prostatic obstruction. The purpose of this study was to evaluate the potency and selectivity of fiduxosin for effects on prostatic intraurethral pressure (IUP) versus mean arterial pressure (MAP) relative to current clinical standards, terazosin and tamsulosin, in conscious dogs. Phenylephrine (PE)-induced increases in IUP and MAP were determined before and at various time points after an oral dose of each antagonist. Hypotensive potency was also determined. All three antagonists caused dose- and time-dependent blockade of the IUP and MAP pressor effects of PE. The IUP ED50 values of fiduxosin, tamsulosin, and terazosin were 0.24, 0.004, and 0.23 mg/kg p.o., respectively. The corresponding MAP ED50 values were 1.79, 0.006, and 0.09 mg/kg p.o. The rank order of IUP selectivity (ratio) was fiduxosin (7.5-fold), tamsulosin (1.5-fold), and terazosin (0.4 = 2.5-fold MAP-selective). Tamsulosin and terazosin caused dose-dependent hypotension, whereas no change in arterial pressure was seen after fiduxosin. These data, illustrating a superior selectivity profile of fiduxosin, are consistent with our hypothesis.
Footnotes
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↵1 In this article, nomenclature used to differentiate among the subtypes of α1-adrenoceptors uses uppercase subscripted letters to describe tissue-sourced receptors and lowercase subscripts to define cloned receptors (Bylund et al., 1994).
- Abbreviations:
- LUTS
- lower urinary tract symptoms
- BPH
- benign prostatic hyperplasia
- BPO
- benign prostatic obstruction
- Ro-70-004
- 3-(3-{4-[fluoro-2-(2,2,2-trifluor-oethoxy)-phenyl]-piperazin-1-yl}-propyl)-5-methyl-1H-pyrimidine-2,4-dione mono hydrochloride monohydrate
- IUP
- intraurethral pressure
- PE
- phenylephrine
- MAP
- mean arterial pressure
- fiduxosin (ABT-980)
- (3-[4-((3aR,9bR)-cis-9-methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrol-2-yl)butyl]-8-phenyl-pyrazino[2′,3′:4,5]thieno [3,2-d]pyrimidine-2,4 (1H,3H)-dione hydrochloride)
- SHR
- spontaneously hypertensive rats
- A-131701
- (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b, hexahydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido[3′,4′:4,5]thieno [3,2-d]pyrimidine-2,4(1H,3H)-dione)
- REC 15/2739
- (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide)
- SNAP 5089
- 5-[[[3-(4,4-diphenyl-1-piperidinyl)propyl]amino]carbonyl]-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)-3-pyridinecarboxylic acid methyl ester
- REC 15/2627
- 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1-oxo-3,3-diphenylpropyl)-piperazine monohydrochloride
- RS 17053
- N-[2-(2-cyclopropyl methoxy phenoxy)ethyl]5-chloro-α,α-dimethyl-1H-indole-3-ethanamine hydrochloride
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- Received July 24, 2001.
- Accepted October 18, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
