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

OBJECTIVE To describe the preclinical pharmacology of Ro 115–1240, a peripherally acting selective α1A/1L-adrenoceptor (AR) partial agonist, compared with the α1A/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 α1A than for α1B and α1D 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 α1-ARs; they acted as selective α1A/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 α1A/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.