LY456236 (hydrochloride)

LY456236 is an antagonist of metabotropic glutamate receptor 1 (mGluR1; IC₅₀ = 140 nM).¹ It reduces the growth of PC-9 non-small cell lung cancer cells and PC-9-AMG cells adapted to mixed-glial culture on soft substrate (MGS) in MGS co-culture but not in monoculture.² It also reduces MGS co-culture-induced increases in EGFR levels in PC-9-AMG cells. LY456236 (50 mg/kg per day) reduces tumor growth in a PC-9-AMG mouse model of brain metastasis. It inhibits seizures in a variety of seizure models, including inhibition of audiogenic clonic-tonic seizures in mice (ED₅₀ = 35 mg/kg).¹ LY456236 (30 and 100 mg/kg) reduces second-phase, but not first-phase, hyperalgesia induced by formalin in mice.³ It also completely reverses mechanical allodynia induced by spinal nerve ligation in rats.

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1. Shannon, H.E., Peters, S.C., and Kingston, A.E. Anticonvulsant effects of LY456236, a selective mGlu1 receptor antagonist. Neuropharmacology 49(Suppl 1), 188-195 (2005).

2. Ishibashi, K., Ichinose, T., Kadokawa, R., et al. Astrocyte-induced mGluR1 activates human lung cancer brain metastasis via glutamate-dependent stabilization of EGFR. Dev. Cell 59(5), 579-594.e576 (2024).

3. Varty, G.B., Grilli, M., Forlani, A., et al. The antinociceptive and anxiolytic-like effects of the metabotropic glutamate receptor 5 (mGluR5) antagonists, MPEP and MTEP, and the mGluR1 antagonist, LY456236, in rodents: A comparison of efficacy and side-effect profiles. Psychopharmacology (Berl) 179(1), 207-217 (2005).