Abstract | OBJECTIVE: To describe the preclinical pharmacology of Ro 115-1240, a peripherally acting selective alpha1A/1L- adrenoceptor (AR) partial agonist, compared with the alpha1A/1L-AR full agonist amidephrine, as AR agonists have some utility in the treatment of stress urinary incontinence (SUI) but are limited by undesirable cardiovascular and central nervous system side-effects. RESULTS: In radioligand-binding studies Ro 115-1240 had greater affinity for alpha1A than for alpha1B and alpha1D subtypes. The potency and intrinsic activity of amidephrine and Ro 115-1240 relative to noradrenaline were determined in native and cell-based assays using human recombinant alpha1-ARs; they acted as selective alpha1A/1L-AR full and partial agonists, respectively. In anaesthetized micropigs and rabbits, amidephrine and Ro 115-1240 produced non-selective, dose-dependent increases in intraurethral and arterial blood pressures but the magnitude of the pressure increases evoked by Ro 115-1240 were about a third of those with amidephrine. In conscious micropigs both agents produced dose-dependent increases in urethral tension. Again, the magnitude of the urethral response to Ro 115-1240 was about a third of that with amidephrine. More importantly, only amidephrine produced dose-dependent increases in blood pressure and decreases in heart rate. Ro 115-1240 produced a maximum increase in urethral tension with no effect on blood pressure or heart rate. CONCLUSION: These results show that by combining selectivity for the alpha1A/1L-AR subtype with a reduction in intrinsic agonist efficacy, Ro 115-1240 has reduced haemodynamic effects while retaining to some degree the contractile effects on urethral smooth muscle. These studies indicate that Ro 115-1240 may be useful as a novel treatment for SUI.
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Authors | D R Blue, D V Daniels, J R Gever, M F Jett, C O'Yang, H M Tang, T J Williams, A P D W Ford |
Journal | BJU international
(BJU Int)
Vol. 93
Issue 1
Pg. 162-70
(Jan 2004)
ISSN: 1464-4096 [Print] England |
PMID | 14678390
(Publication Type: Journal Article)
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Chemical References |
- Adrenergic alpha-1 Receptor Agonists
- Adrenergic alpha-Agonists
- Ethanolamines
- Imidazoles
- Sulfonamides
- amidephrine
- dabuzalgron
- Prazosin
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Topics |
- Adrenergic alpha-1 Receptor Agonists
- Adrenergic alpha-Agonists
(pharmacology, therapeutic use)
- Animals
- Cricetinae
- Dose-Response Relationship, Drug
- Ethanolamines
(pharmacology)
- Female
- Heart Rate
(drug effects)
- Imidazoles
(pharmacology, therapeutic use)
- Male
- Models, Biological
- Prazosin
(metabolism)
- Rabbits
- Sulfonamides
(pharmacology, therapeutic use)
- Swine
- Swine, Miniature
- Urinary Incontinence, Stress
(drug therapy)
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