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N-methyl-D-aspartate (NMDA) receptor antagonists have a potentially wide range of therapeutic applications. Unfortunately, potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in humans and rodents, and thereby produce numerous side effects. However, recent data indicate that moderate-affinity, voltage-dependent, open-channel blockers, such as memantine and neramexane (MRZ 2/579) are useful therapeutics as they prevent the pathological activation of NMDA receptors but allow their physiological activity and should prove to be useful therapeutics in a wide range of CNS disorders. Indeed, memantine was recently registered in both Europe and the USA for the treatment of moderate-to-severe Alzheimer's disease (AD). Neramexane is under development as a potential neuroprotectant against various CNS disorders. Although the predicted therapeutic doses of neramexane were very well tolerated in male volunteers, unfortunately, recent Phase II/III clinical trials for moderate-to-severe AD delivered contradictory results. Neramexane also failed in a recent randomized controlled Phase II trial against drug abuse and depression. Although Phase Ib clinical trials for the indications of chronic pain showed positive results, Phase II results indicate no superiority to existing treatments. However, positive study results have been presented recently in a Phase IIb study on the treatment of tinnitus. A Phase III study for this indication is presently ongoing. Another promising application for neramexane as a neuroprotectant might be chronic neurodegeneration, such as Parkinson's disease, Huntington's disease, vascular dementia, frontal lobe dementia, Down's syndrome and AD.
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