The Novel <scp>TRPV1</scp> Agonist <scp>ST</scp> ‐6631 Improves Swallowing Function in Rat Models of Stroke‐Related Dysphagia and Demonstrates Pharmaceutical Advantage Over Capsaicin, by Exhibiting Minimal Pungent and Irritant Properties

Dysphagia, often associated with neurological disorders such as stroke, not only damages patients' quality of life, like the joy of engaging with meals, but also adversely affects mortality among patients by increasing risks of getting aspiration pneumonia. There are currently no approved drug-based treatments, leaving dysphagic symptom management as unmet clinical needs. Nevertheless, transient receptor potential vanilloid 1 (TRPV1) channel has gained clinical interest to enhance the sensitivity of sensory nerves that facilitate swallowing reflexes in the pharynx. Here, a novel TRPV1 agonist and antedrug candidate ST-6631 has been introduced, with its therapeutic efficacy comparable to the natural ligand capsaicin, in rats operated with permanent bilateral carotid artery occlusion (BCAO), the animal model of stroke-related dysphagia. The ST-6631 antedrug properties have shown rapid metabolism by the hepatic S9 enzymatic fractions, and also shown extremely limited systemic bioavailability in blood circulation after the oral administration in vivo to rats. Furthermore, ST-6631 has been described to possess minimal pungency and irritancy in behavioral sensory assessments in awake rats. ST-6631 has been revealed to provide only a modest form of depolarization in rat sensory dorsal root ganglion (DRG) neurons. In addition, ST-6631 moderately activates the TRPV1 current, characterized by slower but long-lasting waveforms, in the channel-expressing Chinese hamster ovary (CHO) cells. Hence, the present study collectively highlights the pharmaceutically desired product profile of ST-6631, achieving TRPV1 agonism with minimal adverse effects, in clear contrast to the noxious reference ligand, capsaicin.