Epilepsy is one of the most common neurological diseases in the world. Firstly, Epilepsy affects people of all ages, races, social classes, and geographical locations. Secondly, Epilepsy is a disease of the brain characterized by an enduring predisposition to generate seizures and by the neurobiologic, cognitive, psychological, and social consequences of seizure recurrences. However, these epileptic seizures are recurrent paroxysmal events characterized by stereotyped behavioral alterations that reflect the underlying neural mechanisms of the disease. Moreover, Epilepsy can be dangerous when a seizure occurs at certain times. The possibility of drowning and having a car accident is higher. Meanwhile, it is also dangerous when a seizure occurs during pregnancy. Even more, people with epilepsy are more likely to have psychological problems. Research shows that metabotropic glutamate receptor subtype 1 (mGlu1) may be involved in seizure disorders. Hence, we will introduce a mGlu1 receptor antagonist — LY456236.

LY456236 is a selective, non-competitive and orally active mGlu1 receptor antagonist.

LY456236 inhibits phosphoinositide hydrolysis with an IC50 of 0.145 μM. In addition, LY456236 also inhibits EGFR with an IC50 of 0.91 μM.

In vitro, LY456236 (2 μM; 30 min) reduces DHPG-stimulated OCCM-30 proliferation.

In vivo, LY456236 shows anticonvulsant effects in mice (3-100 mg/kg; i.p.; once) and rats (10-60 mg/kg; oral; once). In addition, in male and female DBA/2 mice, LY456236 produces a dose-related inhibition of sound-induced clonic-tonic seizures. Moreover, in male CF1 mice, LY456236 produces a dose-related inhibition of tonic extensor seizures in the threshold electroshock model and limbic seizures in the 6-Hz focal seizure model. Besides, In amygdalaekindled male Sprague Dawley rats, LY456236 produces dose-related decreases in behavioral and electrographic seizures at threshold stimulus intensity.

All in all, LY456236 exhibits good in vivo and in vitro activities in anticonvulsants. Moreover LY456236 may have clinical utility in the treatment of epilepsy and other epilepsy disorders.


[1] Ravikumar B, et al. Cell Chem Biol. 2019 Nov 21;26(11):1608-1622.e6. 

[2] Kanaya S, et al. Connect Tissue Res. 2016 Sep;57(5):417-26.

[3] Shannon HE, et al. Neuropharmacology. 2005;49 Suppl 1:188-95.

[4] Ettore Beghi. Neuroepidemiology 2020;54:185-191.