HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Pharmacological characteristics of Ro 115-1240, a selective alpha1A/1L-adrenoceptor partial agonist: a potential therapy for stress urinary incontinence.

AbstractOBJECTIVE:
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.
AuthorsD 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
JournalBJU international (BJU Int) Vol. 93 Issue 1 Pg. 162-70 (Jan 2004) ISSN: 1464-4096 [Print] England
PMID14678390 (Publication Type: Journal Article)
Chemical References
  • Adrenergic alpha-1 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Ethanolamines
  • Imidazoles
  • Sulfonamides
  • amidephrine
  • dabuzalgron
  • Prazosin
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: