Primidone

Primidone (CAS No. 125-33-7) is a commonly used clinical antiepileptic and anti-essential tremor drug. Its core biological functions include inhibition of the transient receptor potential melastatin 3 (TRPM3) cation channel, inhibition of receptor-interacting protein kinase 1 (RIPK1) kinase activity, non-competitive inhibition of human serum paraoxonase 1 (hPON1), and it has no inhibitory effect on human aromatase (CYP19).

Key activity data: IC₅₀ for TRPM3 inhibition is 0.6–1.2 μM; IC₅₀ for hPON1 inhibition is 0.87 mM, with an inhibition constant Kᵢ of 0.410±0.184 mM; 0.1–1 μM inhibits ~50% of RIPK1 kinase activity, and ≥10 μM completely inhibits RIPK1. In animal studies, it is commonly used for treatment in disease models, including the SOD1G93A amyotrophic lateral sclerosis (ALS) mouse model, the tamoxifen-induced adenomyosis mouse model, and the heat nociception mouse model.

Common applications and concentrations: At the cellular level, 0.1–1 μM is used to inhibit RIPK1 kinase activity, and 0.6–1.2 μM is an effective concentration for TRPM3 inhibition. In animal experiments, ALS mice are given 25 mg/kg/day orally, and adenomyosis mice receive 2 mg/kg/day via intraperitoneal injection. In clinical use, oral administration of 62.5 mg/day in ALS patients can reduce serum RIPK1 and IL-8 levels; for traditional antiepileptic and anti-essential tremor indications, conventional clinical doses are used. At low doses, it can improve symptoms of TRPM3-related neurodevelopmental disorders, and in adenomyosis it can provide analgesia and reduce myometrial infiltration by endometrial tissue.

References:

[1] Jacobsen NW, Halling-Sørensen B, Birkved FK. Inhibition of human aromatase complex (CYP19) by antiepileptic drugs. Toxicol In Vitro. 2008 Feb;22(1):146-53. doi: 10.1016/j.tiv.2007.09.004. Epub 2007 Sep 14. PMID: 17959350.

[2] Beydemir Ş, Demir Y. Antiepileptic drugs: Impacts on human serum paraoxonase-1. J Biochem Mol Toxicol. 2017 Jun;31(6). doi: 10.1002/jbt.21889. Epub 2016 Dec 29. PMID: 28032682.

[3] Wei J, Li M, Ye Z, Hu X, He X, Wang J, Chen G, Zou C, Xu D, Zhang H, Yuan J, Zha Y. Elevated peripheral levels of receptor-interacting protein kinase 1 (RIPK1) and IL-8 as biomarkers of human amyotrophic lateral sclerosis. Signal Transduct Target Ther. 2023 Dec 13;8(1):451. doi: 10.1038/s41392-023-01713-z. PMID: 38086800; PMCID: PMC10716192.

[4] Yin Y, Park CG, Feng S, Guan Z, Lee HJ, Zhang F, Sharma K, Borgnia MJ, Im W, Lee SY. Molecular basis of neurosteroid and anticonvulsant regulation of TRPM3. Nat Struct Mol Biol. 2025 May;32(5):828-840. doi: 10.1038/s41594-024-01463-8. Epub 2025 Jan 14. PMID: 39809942; PMCID: PMC12086041.

[5] Jin Z, Peng Y, Zhang H, He X, Zhang Y, Pan X, Li M, Yang Q. Inhibition of TRPM3 by Primidone Provides a Potential Therapeutic Method for Adenomyosis Management. Drug Des Devel Ther. 2025 Apr 2;19:2533-2549. doi: 10.2147/DDDT.S494981. PMID: 40190806; PMCID: PMC11972583.