Rislenemdaz (MK-0657) (CERC-301) 是一种口服生物可利用的选择性 N-甲基-D-天冬氨酸 (NMDA) 受体亚基 2B (GluN2B) 拮抗剂，其 Ki 和 IC 50 分别为 8.1 nM 和 3.6 nM。
Rislenemdaz (CERC-301) is an orally bioavailable and selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist with Ki and IC 50 of 8.1 nM and 3.6 nM, respectively.
Rislenemdaz (CERC-301) inhibits calcium influx into agonist-stimulating NMDA-GluN1a/GluN2B L(tk-) cells with an IC50 of 3.6 nM. Rislenemdaz exhibits at least 1000× selectivity for the GluN2B receptor versus all targets tested, including the hERG potassium channel. Rislenemdaz also exhibits minimal activity against sigma-type receptors at 10 uM[1].
Rislenemdaz (CERC-301) (1, 3, 10, and 30 mg/kg) significantly decreases immobility frequency (P
[1]. Rachel Garner, et al. Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective N‐methyl‐D‐aspartate receptor antagonist. Pharmacol Res Perspect. 2015 Dec; 3(6): e00198.
Cell experiment: | Rat, dog, rhesus monkey, and human plasma samples (3 mL, N=3) are incubated with 2 and 20 uM [14C] Rislenemdaz at 37°C for 30 min in a shaking water bath. Following incubation, standard ultracentrifugation methodology is used to determine the percentage of drug unbind[1]. |
Animal experiment: | Four groups of 24 rats (12/sex) are given single doses of vehicle (0.5% methylcellulose [MC] and 0.02% sodium lauryl sulfate [SLS] in deionized water) or Rislenemdaz at 10, 30 or 100 mg/kg by oral gavage at a dose volume of 10 mL/kg. Three additional groups of rats (four males and three females per group) are orally dosed in the same manner with Rislenemdaz, and 24h serial blood samples are obtained and analyzed for Rislenemdaz plasma concentrations and evaluated for systemic exposure. Young, adult, male rats are randomly assigned across the treatment groups and are administered vehicle (0.5% MC/0.02% SLS), the reference compound desipramine (20 mg/kg; a tricyclic antidepressant) dissolving in sterile water, or Rislenemdaz (0.1, 0.3, 1, 3, 10, and 30 mg/kg) suspending in 0.5% MC/0.02% SLS, twice on Day 1 (after habituation; ~24 h prior to test, and prior to dark cycle) and once on Day 2 (30 min pretest for desipramine and 45 min pretest for Rislenemdaz and vehicle)[1]. |
参考文献: [1]. Rachel Garner, et al. Preclinical pharmacology and pharmacokinetics of CERC‐301, a GluN2B‐selective N‐methyl‐D‐aspartate receptor antagonist. Pharmacol Res Perspect. 2015 Dec; 3(6): e00198. | |
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