Investigation of α1A‐adrenoceptor reserve in rabbit urethra

The concept of partial agonism and receptor reserve can be applied to target druggable receptors in order to separate therapeutically desirable effects from adverse effects. For treating stress urinary incontinence (SUI) a urethral selective α 1A partial agonist would be ideal. To test urethral selectivity of α 1A partial agonists, we used rabbit urethra, bladder neck, mesenteric artery & vein to study potency (pEC 50 ) and efficacy (E max ) of RO1151240 and RO1154494; two structurally related α 1A ‐adrenoceptor partial agonists. Our compounds did not induce significant contractility in the mesenteric vein. However, similar to the full agonist Norepinephrine (NE) the rank order of intrinsic activity of Amidephrine (Ami, a selective α 1A agonist), RO1151240 & RO1154494 was urethra > mesenteric artery > bladder neck indicating that the urethra has the most functional α 1A receptor reserve. The effect of NE was through α 1A receptors as NE‐induced contractions were attenuated by the α 1A selective antagonist RO1100329 (10 nM) with high affinity estimates (pA 2 between 9.4‐9.6). Our hypothesis of greater α 1A ‐adrenoceptor functional reserve in rabbit urethra contributing to urethral selectivity was further tested by incubating tissues with the irreversible alkylating agent phenoxybenzamine (PBZ), followed by drug treatment. As expected, 10 nM PBZ attenuated the response to NE and Ami in the bladder neck & mesenteric artery to a greater extent than in the urethra. Extrapolating these results to human tissues, one may rationally hypothesize that it is possible to target urethral α 1A ‐adrenoceptors with partial agonists for SUI, without vascular liabilities.