JW-65 is a selective TRPC3 channel inhibitor with favorable blood-brain barrier penetration. JW-65 directly binds to human TRPC3 protein and modulates calcium signaling to reduce seizure susceptibility. JW-65 reduces seizure incidence, severity, and duration while prolonging seizure latency in multiple seizure models. JW-65 alleviates Aβ‑induced neuronal damage. JW-65 serves as a valuable tool for research on epilepsy, seizure disorders, and Alzheimer’s disease [1] [2] [3].
In Vivo, JW-65 (5-40 mg/kg; i.p.; single dose) dose-dependently reduces acoustically-evoked seizure incidence, latency, duration, and severity in male and female GEPR-3 rats, with females exhibiting greater sensitivity[1]. JW-65 (10 mg/kg; i.p.; daily; 5 consecutive days) completely suppress acoustically-evoked seizures in male and female GEPR-3 rats[1]. Pretreatment with JW-65 (100 mg/kg; i.p.; once daily for 2 consecutive days, plus a third dose on experiment day 15 minutes before Pilocarpine injection) substantially impairs the initiation and development of Pilocarpine-induced status epilepticus in mice[3]. Post-seizure onset treatment with JW-65 (100 mg/kg; i.p.; single dose administered after Stage 2 seizure onset) mitigates the progression of Pilocarpine-induced status epilepticus in mice, preventing all treated mice from developing long-lasting status epilepticus and reducing electrographic seizure activity[3]. JW-65 (20-100 mg/kg; i.p.; single dose 30 minutes before PTZ injection) reduces susceptibility to PTZ-induced seizures in mice in a dose-dependent manner[3].
In Vitro, JW-65 (0.001-10 μM) potently inhibits hTRPC3-mediated currents in HEK293 cells, with IC50 values of 0.37 μM (no extracellular Ca2+)[2]. JW-65 (10 μM) is a selective inhibitor of hTRPC3 over other TRP channel family members, showing no inhibition of hTRPA1, rTRPV1, rTRPV4, or hTRPM8, and only partial inhibition of closely related hTRPC6 (39%) and hTRPC7 (26%) at 10 μM[2]. JW-65 exhibits significantly improved metabolic stability over Pyr3, with a half-life of more than 4 hours in mouse, rat, and human liver microsomes[2][3].
References:
[1]. Silva-Cardoso GK, et al. Inhibition of TRPC3 channels suppresses seizure susceptibility in the genetically-epilepsy prone rats. Eur J Pharmacol. 2024;977:176722.
[2]. Zhang S, et al. Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity. ACS Med Chem Lett. 2021;12(4):572-578. Published 2021 Mar 5.
[3]. Nagib MM, et al. Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects. Epilepsia. 2022;63(4):1003-1015.
In Vivo, JW-65 (5-40 mg/kg; i.p.; single dose) dose-dependently reduces acoustically-evoked seizure incidence, latency, duration, and severity in male and female GEPR-3 rats, with females exhibiting greater sensitivity[1]. JW-65 (10 mg/kg; i.p.; daily; 5 consecutive days) completely suppress acoustically-evoked seizures in male and female GEPR-3 rats[1]. Pretreatment with JW-65 (100 mg/kg; i.p.; once daily for 2 consecutive days, plus a third dose on experiment day 15 minutes before Pilocarpine injection) substantially impairs the initiation and development of Pilocarpine-induced status epilepticus in mice[3]. Post-seizure onset treatment with JW-65 (100 mg/kg; i.p.; single dose administered after Stage 2 seizure onset) mitigates the progression of Pilocarpine-induced status epilepticus in mice, preventing all treated mice from developing long-lasting status epilepticus and reducing electrographic seizure activity[3]. JW-65 (20-100 mg/kg; i.p.; single dose 30 minutes before PTZ injection) reduces susceptibility to PTZ-induced seizures in mice in a dose-dependent manner[3].
In Vitro, JW-65 (0.001-10 μM) potently inhibits hTRPC3-mediated currents in HEK293 cells, with IC50 values of 0.37 μM (no extracellular Ca2+)[2]. JW-65 (10 μM) is a selective inhibitor of hTRPC3 over other TRP channel family members, showing no inhibition of hTRPA1, rTRPV1, rTRPV4, or hTRPM8, and only partial inhibition of closely related hTRPC6 (39%) and hTRPC7 (26%) at 10 μM[2]. JW-65 exhibits significantly improved metabolic stability over Pyr3, with a half-life of more than 4 hours in mouse, rat, and human liver microsomes[2][3].
References:
[1]. Silva-Cardoso GK, et al. Inhibition of TRPC3 channels suppresses seizure susceptibility in the genetically-epilepsy prone rats. Eur J Pharmacol. 2024;977:176722.
[2]. Zhang S, et al. Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity. ACS Med Chem Lett. 2021;12(4):572-578. Published 2021 Mar 5.
[3]. Nagib MM, et al. Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects. Epilepsia. 2022;63(4):1003-1015.