Discovery of Dual TRPA1 and TRPV1 Antagonists as Novel Therapeutic Agents for Pain

• Published in: Pharmaceuticals (Basel, Switzerland) Switzerland), 2024-09, Vol.17 (9), p.1209
• Main Authors: Do, Nayeon, Zuo, Dongxu, Kim, Miri, Kim, Minseok, Ha, Hee-Jin, Blumberg, Peter M, Ann, Jihyae, Hwang, Sun Wook, Lee, Jeewoo
• Format: Article
• Language: English
• Subjects: Acids; analgesic; Analgesics; Analysis; Carbon; Care and treatment; Dosage and administration; Dose-response relationship (Biochemistry); Drug development; dual antagonist; Health aspects; Hyperalgesia; Inflammation; Ion channels; Oral administration; Pain; Pharmacokinetics; Physiological aspects; Scientific equipment and supplies industry; Side effects; Testing; TRPA1; TRPV1
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph17091209

Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound demonstrated dose-dependent analgesic activity with an ED of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.