YM-202074

YM-202074 is a selective, allosteric metabotropic glutamate receptor type 1 (mGluR1) antagonist with high affinity. YM-202074 binds to the allosteric site of rat mGluR1 with a K_i of 4.8 nM. YM-202074 fumarate also inhibits mGluR1-mediated inositol phosphate production in rat cerebellar granule cells with an IC₅₀ of 8.6 nM. YM-202074 has potent neuroprotective effects in transient MCA (tMCA) occlusion rat models^[1]. In Vitro:YM-202074 significantly inhibits the mGluR1-mediated inositol phosphates production in rat cerebellar granule cells with an IC₅₀ of 8.6 nM^[1].
YM-202074 shows specific selectivity over other mGluRs, such as without agonistic nor antagonistic activity on mGluR2, mGluR3, mGluR4a, mGluR6 or mGluR7b (≤ 10 μM), but inverse agonistic activity on mGluR5 (10 μM) in HEK cells and CHO cells^[1].
YM-202074 shows no affinity for ionotropic glutamate receptors (≤ 10 μM) and moderate off-target activity at a few receptors, such as with >60% inhibition of Adrenaline α2C receptor, dopamine transporter, acetylcholine M2/M4 receptor, sigma2 receptor, sodium channel site 2, and ≤ 50% inhibition of other 74 sites^[1].
In Vivo:YM-202074 (i.v. infusion, 5 mg/kg/h for 8 h or 20 mg/kg/h for 0.5 h followed by 5 mg/kg/h for 7.5 h) rapidly reaches the brain, achieving a free concentration of approximately 0.3 μM within 12 minutes and a steady-state phase within 1.5 hours with the loading infusion of 20 mg/kg/h for 0.5 h^[1].
YM-202074 (i.v. infusion, 10-20 mg/kg/h for 0.5 h followed by 2.5-5 mg/kg/h for 0.5-6 h) provides neuroprotection independent of nonspecific factors such as hypothermia, with no significant Physiological variables in tMCA occlusion rat models^[1].
YM-202074 (i.v. infusion, 10-20 mg/kg/h for 0.5 h followed by 2.5-5 mg/kg/h for 23.5 h) dose-dependently improves neurological deficit and reduces the infarct volume in both the hemisphere and cortex in tMCA occlusion rat models, with potent efficacy in high dose^[1].
YM-202074 (i.v. infusion, 20 mg/kg/h for 0.5 h followed by 5 mg/kg/h from 2 or 3 h to 24 h after tMCA occlusion) significantly maintains neuroprotection even when given 2 h after the onset of ischemia in tMCA occlusion rat models^[1].
YM-202074 (i.v. infusion, 20 mg/kg/h for 0.5 h followed by 5 mg/kg/h from 2h to 24 h week after tMCA occlusion) notably sustains the improvement of neurological deficit and the reduction of infarct volume as well as increase of rat body weight for 1 week following the onset of ischemia in tMCA occlusion rat models^[1].