Abstract
Benign prostatic hyperplasia (BPH), common in aging males, is often treated with α1-adrenoceptor antagonists. To minimize hypotensive and other side effects, compounds with selective antagonist activity at α1A- and α1D- (compared with α1B-) adrenoceptors were evaluated that would block lower urinary tract α1-adrenoceptors in preference to cardiovascular α1B-adrenoceptors. Fiduxosin (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; ABT-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 α1a- (0.16 nM) and α1d-adrenoceptors (0.92 nM) in radioligand binding studies compared with α1b-adrenoceptors (25 nM) or in isolated tissue bioassays [pA2 values of 8.5–9.6 for α1A-receptors in rat vas deferens or canine prostate strips, 8.9 at α1D-adrenoceptors (rat aorta), compared with 7.1 at α1B-adrenoceptors (rat spleen)]. Furthermore, the compound antagonized putative α1L-adrenoceptors in the rabbit urethra (pA2value of 7.58). Fiduxosin blocked epinephrine-induced increases in canine IUP (pseudo-pA2 value of 8.12), eliciting only transient decreases in mean arterial blood pressure (MAP) in SHR. The area under the curve (AUC0→60 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 α1A- and α1D- versus α1B-adrenoceptors in vitro, blockade of putative α1L-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.
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).
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Portions of these data were presented at the American Urological Association 2000 Meeting [Hancock A, Meyer M, Brune M, Buckner S, Esbenshade T, Drizin I, Sullivan J, Williams M, and Kerwin J (2000) Fidoxosin: An α1a/d receptor antagonist with enhanced in vivo urolselectivity relative to terazosin and tamsulosin. J Urol 163 (Suppl 4):310].
- Abbreviations:
- BPH
- benign prostatic hyperplasia
- REC 15/2739
- (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxamide)
- Ro-70-0004
- 3-(3-{4-[fluoro-2-(2,2,2-trifluoroethoxy)-phenyl]-piperazin-1-yl}-propyl)-5-methyl-1H-pyrimidine-2,4-dione mono hydrochloride monohydrate
- 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)
- DMSO
- dimethyl sulfoxide
- PE
- phenylephrine
- IUP
- intraurethral pressure
- EPI
- epinephrine
- SHR
- spontaneously hypertensive rats
- MAP
- mean arterial blood pressure
- AUC
- area under the curve
- pED50
- 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
- Ki
- inhibition constant as a measure of drug affinity for a receptor, equivalent to the concentration of compound required to occupy 50% of receptors
- pKB
- negative logarithm of the dissociation constant
- pA2
- negative logarithm of the concentration of compound required to elicit a 2-fold shift of an agonist concentration-response curve in isolated tissues
- 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)
- CL
- confidence limit
- B8805-033
- [(±)-1,3,5-trimethyl-6-[[3-[4-((2,3dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]pro-pyl]amino]-2,4(1H,3H)-pyrimidin-one]
- WB-4101
- [2-(2,5-dimethyoxyphenoxyethyl)-aminomethyl-1,4 benzodioxane
- BMY-7378
- (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-1-7,9-dione)
- RWJ-38063
- [N-(2-{4-[2-(methylethoxy)phenyl]piperazinyl}ethyl-2-(2-oxopiperadinyl)acetamide]
- RWJ-69736
- [N-(3-{4-[2-(methylethoxy)phenyl]piperazinyl}propyl-2-(2-oxopiperadinyl)acetamide]
- Received July 24, 2001.
- Accepted October 19, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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