Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models

Metabotropic glutamate receptor 1 (mGlu1 receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu1 receptor antagonist, (R)-N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3-d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu1 receptor blockade. YM-230888 bound an allosteric site of mGlu1 receptor with a Ki value of 13 ± 2.5 nM and inhibited mGlu1-mediated inositol phosphate production in rat cerebellar granule cells with an IC50 value of 13 ± 2.4 nM. It showed selectivity for mGlu1 versus mGlu2–mGlu7 subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED50 value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu1 receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu1 receptors.