The Diversity of Mechanisms of Blockade of Ion Channels as a Pathway to the Design of New Pharmacological Agents.

Impairments to glutamatergic synaptic transmission are seen in many pathological CNS states. Excess glutamate actions, inducing persistent depolarization of neurons and massive calcium influx, can lead to cell death. Despite the obvious importance of developing antiglutamate agents as neuroprotectors, the only one of the ionotropic glutamate receptor antagonists which has been introduced into practice is memantine. One of the causes of the multiple side effects occurring when glutamate receptor antagonists are used is that these pharmacological agents inhibit the whole of the receptor pool, both those receptors involved in pathological processes and those performing normal physiological functions. One possible approach to overcoming this problem consists of developing pharmacological agents whose actions are enhanced in potential pathological states, such as high-frequency stimulation of receptors, high glutamate concentrations, decreases in neuron membrane potential, etc. The efficacies of many types of antagonists, such as channel blockers, depends on the membrane potential and the nature of receptor activation. The present article provides a discussion of some of the characteristics of the mechanisms of blockade of glutamate receptor ion channels from the point of view of the potential to create neuroprotective agents. In particular, blockers with different interactions with channel gate structures and different types of blockade voltage dependence are compared, with analysis of the characteristics of the actions of blockers able to penetrate channels to enter cells. We suggest that only detailed study of the mechanisms of action of antagonists on glutamate receptors can bring us towards the ability to predict the results of using blockers in vivo on the basis of data obtained in vitro. [ABSTRACT FROM AUTHOR]