Additional Information and References for Physicians (Page 2)

In comparison to the reference non-competitive NMDA antagonist, MK-801, there are some significant differences with NST-001.  In terms of neuroprotection, the two drugs are equally effective at protecting cultured hippocampal neurons⁴⁵.  NMDA receptors are heteromeric receptors containing at least one NRI subunit and one of four NR2 subunits (NR2A-D).  In HEK cells expressing NRIA/2A combinations, NST-001 and MK-801 have similar potencies at inhibiting NMDA-induced currents, but NST-001 inhibits only 53 % of these currents whereas MK-801 blocks 100 %.  On NR1A/NR2B receptors, NST-001 and MK-801 were able to totally inhibit NMDA-induced currents, however NST-001 had a 6-fold weaker affinity than MK-801.⁴⁵ Taking into account the subcellular localization of both NMDAR subtypes, the differential effect of MK-801 and NST-001 on these receptors could explain both their similarities in terms of neuroprotective properties and their differences in terms of intrinsic neurotoxicity.  One of the concerns with MK-801 and other potent NMDA antagonists is that they have been shown to induce neuronal vacuolization and toxicity in rodents⁴⁶.

Reference:

45.     Vandame D, Desmadryl G, Becerril Ortega J, Teigell M, Crouzin N, Buisson A, Privat A, Hirbec H (2007) Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11, J Neurochem 103:1682-1696.

46.     Olney JW (2002) New insights and new issues in developmental neurotoxicology, Neurotoxicology 23:659-668.