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 Gq 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.