RESUMEN
This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure-activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.
Asunto(s)
Piel , Canal Catiónico TRPA1 , Canal Catiónico TRPA1/antagonistas & inhibidores , Canal Catiónico TRPA1/metabolismo , Humanos , Relación Estructura-Actividad , Piel/efectos de los fármacos , Piel/metabolismo , Animales , Estructura Molecular , Relación Dosis-Respuesta a Droga , Células HEK293RESUMEN
BACKGROUND: Recent changes in regulatory restrictions and social opposition to animal toxicology experiments have driven the need for reliable in vitro tests for predicting the skin sensitizing potentials of a wide variety of industrial chemicals. Previously, we developed the human cell line activation test (h-CLAT) as a cell-based assay to predict the skin sensitizing potential of chemicals, and showed the correspondence between the h-CLAT and the murine local lymph node assay results. OBJECTIVES: This study was conducted to investigate the predictive performance of the h-CLAT for human skin sensitizing potential. MATERIALS/METHODS: We selected a total of 66 test chemicals with known human sensitizing potential, and tested all chemicals with the h-CLAT. We then evaluated the performance of the h-CLAT in predicting human sensitizing potential. RESULTS AND CONCLUSION: Forty-five of 51 tested sensitizers were positive in the h-CLAT, indicating relatively high sensitivity. Also, 10 of 15 non-sensitizers were correctly detected as negative. The overall agreement between human data and h-CLAT outcome was 83%. Furthermore, the h-CLAT could accurately predict the human sensitizing potential of 23 tested chemicals that were amines, heterocyclic compounds, or sulfur compounds. Our data indicate the utility of the h-CLAT for predicting the human skin sensitizing potential of a variety of chemicals.