NMDA receptor antagonist 2 is a highly potent and orally active NR2B subtype-selective antagonist of the N-methyl-D-aspartate (NMDA) receptor, with an IC50 of 1.0 nM and a Ki value of 0.88 nM. This compound is valuable in scientific investigations of neuropathic pain and Parkinson’s disease.

NMDA NR2B:0.88 nM (Ki)

NMDA receptor antagonist 2 demonstrates remarkable efficacy and selectivity, displaying potent inhibition towards NR2B with a Ki value of 0.88 nM and significant selectivity against hERG binding (IP=20000 nM). Its effectiveness is further evidenced in a Ca2+ flux assay using cells with recombinant NR1/NR2B receptors, and its hERG-channel selectivity is confirmed via an MK-499-binding assay. Additionally, this compound maintains its potency in both a functional assay with NR2B-expressing cells (IC50=1.0 nM) and a binding assay on human temporal cortex homogenate (Ki=0.81 nM). In electrophysiology assays, Compound 22 achieves complete ion flux blockade across NR2B receptors with a KD of 0.35 nM. It also demonstrates substantial selectivity over NR2A (IC50=200 μM), hERG binding (IP=20 μM), α-adrenergic receptors (IC50>100 μM), and several CYP P450 isoenzymes including CYP3A4, 2C9, and 2D6.

In pharmacokinetic studies, NMDA receptor antagonist 2 demonstrated favorable pharmacological properties across different species. In dogs, it exhibited excellent oral bioavailability (F=83%), a half-life (T 1/2 =7.5 hours), and a clearance rate (CL=3.6 mL/min/kg). In contrast, rhesus monkeys showed a moderate clearance rate (CL=12 mL/min/kg) and lower oral bioavailability (F=17%), with a significantly shorter half-life (T 1/2 =1.5 hours). Rats presented an oral bioavailability (F=23%), a brief half-life (T 1/2 =0.7 hours), and a higher clearance rate (CL=24 mL/min/kg), with an ED50 for receptor occupancy at 4.8 mg/kg following oral administration. Furthermore, in a rat spinal nerve ligation model to simulate neuropathic pain, NMDA receptor antagonist 2 effectively inhibited tactile allodynia in a dose-dependent manner, significantly improving the condition by 15% (3 mg/kg), 41% (10 mg/kg), and 69% (30 mg/kg) compared to the control group. Similarly, in an acute rodent model of Parkinson’s disease, oral administration of NMDA receptor antagonist 2 reduced haloperidol-induced catalepsy, improving scores by 34% (3 mg/kg), 86% (10 mg/kg), and 92% (30 mg/kg), establishing its dose-dependent efficacy.