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

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.

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.

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.