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 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.


CONCLUSIONS
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.
Blue
D R
DR
Roche Palo Alto, Palo Alto, CA, USA. dave.blue@roche.com
Daniels
D V
DV
Gever
J R
JR
Jett
M F
MF
O'Yang
C
C
Tang
H M
HM
Williams
T J
TJ
Ford
A P D W
AP
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008954:Models, Biological; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013552:Swine; D013556:Swine, Miniature; D014550:Urinary Incontinence, Stress / Q000188:drug therapy*
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D004983:Ethanolamines; D007093:Imidazoles; D013449:Sulfonamides; C016980:amidephrine; C481520:dabuzalgron; D011224:Prazosin