Basimglurant sulfate

Basimglurant (RG7090; RO4917523) sulfate is a selective, orally bioavailable negative allosteric modulator of the metabotropic glutamate receptor 5 (mGluR5) that can cross the blood-brain barrier. It exhibits a Ki of 1.4 nM for [³H]-ABP688 and 35.6 nM for [³H]-MPEP. Basimglurant sulfate inhibits mGlu5-mediated signaling pathways and receptor constitutive activity, modulates nucleus accumbens dopamine levels, and exerts anxiolytic, antidepressant-like, analgesic, and wakefulness-promoting effects, while altering δ-wave power during non-rapid eye movement sleep. It is applicable in research related to depression, fragile X syndrome, and anxiety disorders.

Basimglurant sulfate exhibits low metabolic stability in rat liver microsomes (11 μL/min/mg) while maintaining good stability in human liver microsomes (CL <10 μL/min/mg). It shows no teratogenic potential in embryonic stem cell assays. Basimglurant sulfate strongly inhibits the binding of [3H]-MPEP to human, mouse, and rat mGlu5 receptors, with K i values of 35.6 nM, 29.5 nM, and 33.2 nM, respectively. It effectively inhibits quisqualate-induced calcium mobilization in mGlu5-expressing HEK293 cells from humans, mice, and rats, with IC 50 values of 7.0 nM, 8.88 nM, and 7.48 nM, respectively. Additionally, basimglurant sulfate inhibits the accumulation of IP in quisqualate-stimulated mGlu5-expressing HEK293 cells from humans, mice, and rats, with IC 50 values of 5.85 nM, 4.98 nM, and 5.93 nM. It also acts as an inverse agonist of the human mGlu5 receptor, with an IC 50 of 38.1 nM.

Basimglurant sulfate demonstrates significant antidepressant activity in rats undergoing anhedonia induced by chronic mild stress when administered intraperitoneally at 1-3 mg/kg daily for 21 days. Administered orally at 10-30 mg/kg three times within 24 hours, it produces antidepressant effects in the forced swimming test in rats. When given orally at 1-30 mg/kg as a single dose, it induces brain activity patterns similar to conventional antidepressants in rats. In the rat Vogel conflict test, oral administration of 0.03-0.3 mg/kg as a single dose exhibits anxiolytic activity. In mice, it exerts anxiolytic effects in the stress-induced hyperthermia test when administered orally at 0.01-1 mg/kg as a single dose. In rats, it shows anxiolytic activity in the conditioned emotional response test and the fear-potentiated startle experiment with oral doses of 0.3-1 mg/kg and 0.1-1 mg/kg, respectively, in a single dose. Furthermore, oral administration of 10 mg/kg as a single dose demonstrates analgesic activity during the late phase of the formalin-induced pain model in mice. Subcutaneous administration of 0.1-10 mg/kg inhibits cold allodynia in sciatic nerve-ligated rats in a dose-dependent manner, while intravenous administration of 0.03-0.3 mg/kg increases micturition threshold volume in anesthetized rats dose-dependently. Additionally, intravenous administration of 0.01-0.03 mg/kg significantly reduces bladder contraction frequency in anesthetized rats. In Norwegian rats, oral administration of 0.03-0.3 mg/kg daily for five days during the active dark phase elicits a dose-dependent wakefulness-promoting effect, decreasing REM and non-REM sleep, prolonging sleep latency, and enhancing δ wave power in non-REM sleep.