Therapeutic potential of PCP receptor ligands

Abstract

Pharmacological control of excitatory pathways responding to the neu retransmitter L-glutamate in the central nervous system (CNS) is an exceedingly important goal, yet to be achieved in a clinically useful and safe fashion. One approach is the development of compounds that can modulate the excessive activation of N-methyl-D-aspartate (NMDA) receptors by glutamate during ischaemic events such as stroke. Certain compounds can effect this modulation, known as neuroprotection, by binding to the phencyclidine (PCP) receptor, which is located within an ion channel associated with the NMDA receptor. These ion channel blockers impede inward calcium ion flux and thus antagonise the agonist action of glutamate. This goal is particularly valuable as it relates to preventing the spread of neuronal degradation that is part of the pathological process associated with ischaemia, the result being improved neurological outcome of patients. At least three drugs are currently being evaluated in clinical trials for treatment of ischaemia, to be administered in the therapeutic window that exists for a few hours after the onset of ischaemia: Cerestat®, a diarylguanidine by Cambridge Neuroscience; dextrorphan, a dextromethorphan metabolite being pursued by Hoffman-LaRoche; and remacemide, an N-glycinated diphenylethylamine, being tested by Fisons. The adamantane derivative, memantine, has shown significant promise at the pre-clinical level for treatment of ischaemia, and has already been in clinical use for over a decade in treatment of Parkinson's disease. It is likely that clinical trials of memantine for ischaemia treatment will begin soon. Some of the clinical trial results are quite promising, for example, putative neuro-protective concentrations have been achieved with low CNS side effects. Given the promising early clinical trial results, extensive preciinical testing, and the huge potential benefit, it is predicted that the use of PCP receptor iigands will achieve clinically useful status in the near future for treatment of stroke and traumatic head injury.