The present invention relates to a method of inhibiting N-methyl-D-aspartate (NMDA) glutamate receptor-mediated ion channel activity (NMDA receptor activity), comprising contacting a neuronal cell (e.g., hippocampal neuron, spinal cord cell) with an effective amount (e.g., 1 to 500 mu M) of a derivative of pregnenolone sulfate. Derivatives of pregnenolone sulfate that inhibit NMDA receptor activity include pregnenolone sulfate derivatives in which the A ring includes at least one double bond; PS in which the A ring is fully unsaturated; PS derivatives in which the double bond at the C5-C6 position is reduced; and PS in which the moiety at the C3, C5, C6, C7, C11, C17, C20 and/or C21 position is modified. It further relates to PS derivatives which have modifications at other positions (e.g., C10, C10, C13, C18, C19), alone or in combination, and are inhibitors of NMDA receptor activity. The present invention also relates to a method of modulating or altering (e.g., potentiating; inhibiting) excitatory glutamate-mediated synaptic activity comprising contacting neurons with pregnenolone sulfate and derivatives of pregnenolone sulfate. The present invention also relates to a method of treating a disease associated with L-glutamate-induced NMDA receptor activation selected from the group consisting of: neuropathic pain, drug withdrawal/dependency, epilepsy, glaucoma, chronic neurodegenerative diseases, amyotrophic lateral sclerosis, anxiety disorders, brain cell death, ischaemia, stroke, trauma in a host comprising administering to the host an effective amount of a derivative of pregnenolone sulfate.
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