The functions of melatonin, a hormone that regulates sleep and various physiological processes, are primarily mediated via activation of the high-affinity G protein-coupled melatonin receptors, termed MT1 and MT2 (Reppert et al., 1994, 1995). We previously reported that MT1 and MT2 receptor mRNA were highly expressed in human and rat female urethra and that stimulation of MT1 receptors caused smooth muscle contraction through a Gq protein-dependent pathway in rat urethral tissue but not in other smooth muscle tissues such as artery and bladder (Matsui et al., 2025). Our in vivo studies also revealed that melatonin analogs increased urethral pressure in rats (Matsui et al., 2025). These results led us to consider the possibility of utilizing the urethral contractile effect of MT1 receptor activation for the treatment of urological disorders.

The major function of urethral muscles is to maintain urinary continence by contracting during the urine storage phase and relaxing during the voiding phase. Dysfunction of the urethral muscles is associated with urological disorders. Stress urinary incontinence (SUI), defined as involuntary loss of urine on effort of physical exertion (e.g sporting activities) or on sneezing or coughing (Haylen et al., 2010), is a major urological problem, especially in women. Although the pathophysiology of SUI is not fully understood, the two main pathogenic factors are considered to be urethral hypermobility and intrinsic sphincter deficiency (ISD) (Yoshimura and Miyazato, 2012). Urethral hypermobility is excessive movement of the urethra due to the loss of urethral support associated with anatomical changes in the pelvic floor. ISD is an inability of the urethral sphincter to contract. These conditions are attributed to pregnancy, childbirth and aging, and often coexist. (Yoshimura and Miyazato, 2012; Jefferson and Linder, 2024). In SUI patients, coughing, sneezing and lifting heavy objects produces a sudden elevation in abdominal and bladder pressure, resulting in the leakage of urine due to insufficient urethral resistance. Accordingly, one of the aims of pharmacotherapy for SUI has been to increase urethral resistance by contracting urethral striated muscle and/or smooth muscle.

Duloxetine, a serotonin-noradrenaline reuptake inhibitor, increases urethral pressure through urethral striated muscle contraction and thereby improves symptoms in SUI patients (Bump et al., 2008). Substantial efforts have also been made to investigate the clinical effects of α1-adrenoceptor agonists, which contract urethral smooth muscle, for SUI. Nevertheless, no globally approved pharmacotherapy for SUI has yet been developed.

ASP5633 (3-(2-acetamidoethyl)-6-fluoro-5-methoxy-N-methyl-1H-indole-2-carboxamide; Fig. 1) is a novel peripherally restricted MT1 and MT2 receptor agonist discovered by Astellas Pharma Inc. (Tokyo Japan). Here, to investigate the potential of MT1 receptor stimulation for the treatment of SUI, we examined the effects of ASP5633 on urethral continence function and normal voiding function in female rats.