Effect of ASP5633, a novel peripherally restricted MT₁/MT₂ receptor agonist, on urethral function in female rats

Melatonin is a hormone that regulates numerous physiological processes through activation of specific G protein-coupled receptors, termed MT₁ and MT₂ receptors. We previously reported that stimulation of MT₁ receptors in female rat urethra activated intracellular Ca²⁺ mobilization via a G_q protein-dependent pathway, resulting in urethral smooth muscle contraction. This study aimed to investigate the potential of MT₁ receptor-related urethral contraction in the treatment of urological disorders using ASP5633 (3-(2-acetamidoethyl)-6-fluoro-5-methoxy-N-methyl-1H-indole-2-carboxamide), a novel peripherally restricted MT₁/MT₂ receptor agonist. ASP5633 exhibited potent and selective agonistic activities for MT₁ and MT₂ receptors and induced urethral contraction in an isolated rat tissue strip study. Pharmacokinetic and pharmacodynamic studies of sleep and wake stages demonstrated that ASP5633 is a peripherally restricted melatonin receptor agonist. ASP5633 increased urethral pressure in the bladder filling phase only, and not in the voiding phase, and did not affect voiding efficiency in female rats. ASP5633 increased urethral resistance, thereby raising the bladder pressure threshold required to cause fluid leakage from the bladder in anesthetized female rats. These results from non-clinical studies suggest that ASP5633 has the potential to attenuate urine leakage induced by sudden elevation of abdominal and bladder pressure without impairing voiding function or causing central nervous system-related side effects.