Pharmacological Properties of 2-((R-5-Chloro-4-methoxymethylindan-1-yl)-1H-imidazole (PF-3774076), a Novel and Selective α1_A-Adrenergic Partial Agonist, in in Vitro and in Vivo Models of Urethral Function

Abstract

2-((R-5-Chloro-4-methoxymethyl-indan-1-yl)-1H-imidazole (PF-3774076) is a central nervous system (CNS) penetrant, potent, selective, partial agonist at the human ␣1 A -adrenoceptor, demonstrating efficacy and selectivity in a range of binding and functional assays. In vivo, PF-3774076 increases peak urethral pressure in anesthetized female dogs in a dosedependent manner, inducing changes in both the proximal and distal portions of the urethra via a central mechanism of action. The profile of this compound suggests that a CNS penetrant partial agonist at the ␣1 A -adrenoceptor may offer significant benefit in stress urinary incontinence (SUI). However, despite partial agonism at the ␣1 A -adrenoceptor and selectivity over ␣1 B -and ␣1 D -adrenoceptors, PF-3774076 did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function. This may be due to activation of both peripheral and central ␣1 A -adrenoceptors. These data indicate that although central, partial ␣1 A -agonists may offer significant benefit in the treatment of SUI, it may not be possible to achieve the desired level of urethral selectivity over cardiovascular events with this class of agent.

Nitrergic relaxations and phenylephrine contractions are not compromised in isolated urethra in a rat model of diabetes

“…2), with the highest amplitude of contractions in the mid region of the rat urethra. This is in line with previous studies that investigated responses to PE or other α1-AR agonists in vitro and in vivo, in the rat and other species and have shown region and species dependent variations of responses along the length of the urethra (Maggi et al, 1989;Walters et al, 2006;Yang et al, 2007;Conlon et al, 2009). For example, in the rat the highest amplitude responses were found in the proximal urethra and minimal contractile responses were found in the distal urethra, while in the guinea pig the opposite trend was shown, with the highest amplitude of contractions presented at the distal end (Walters et al, 2006).…”

Role of vasopressin V1Areceptor in the urethral closure reflex in rats

“…Recent studies using pharmacological agents reveal that 5-HT 2 receptors and ␣ 1A -adrenoceptors are involved in the urethral closure reflex (2,17,18). However, few findings have elucidated the enhancement of urethral resistance through the urethral closure reflex at the spinal cord excluding serotonin or norepinephrine pathways.…”

Salutary effect of gastric pentadecapeptide BPC 157 in two different stress urinary incontinence models in female rats

“…To date, no standard agents have been shown to improve healing of severely injured or transected muscle to support the effect on stress urinary incontinence (SUI), nor has this possibility been considered from theoretical or practical points of view [1–6]. …”

“…In addition, particular combinations (alpha2-adrenoceptor blockade and duloxetine) [3] and various other possibilities were suggested (eg, angiotensin II) [4]. Most improvements of therapy (e.g., alpha-agonists) aim to selectively (eg, sub-type-selective alpha1-adrenoceptor agonists) affect urethral pressure, peripherally [5], and most recently, centrally [6], and these therapies may affect the bladder or urethral properties of healthy subjects (e.g., selective, partial agonist at the human alpha1(A)-adrenoceptor) [6], explaining the elevation in leak point pressure (LPP). This approach did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function [4–6,20].…”

“…Most improvements of therapy (e.g., alpha-agonists) aim to selectively (eg, sub-type-selective alpha1-adrenoceptor agonists) affect urethral pressure, peripherally [5], and most recently, centrally [6], and these therapies may affect the bladder or urethral properties of healthy subjects (e.g., selective, partial agonist at the human alpha1(A)-adrenoceptor) [6], explaining the elevation in leak point pressure (LPP). This approach did not offer the necessary degree of separation over cardiovascular events when assessed in in vivo models of cardiovascular function [4–6,20]. Moreover, since a synergistically improved continence rate with a combination of physiotherapy [1,2] and pharmacological treatment (e.g., with duloxetine) [22], it is therefore more surprising that none of the standard agents was shown to improve the healing of severely injured or transected muscle to support the effect on SUI.…”