Rat brain synaptosomal membranes that are depleted of endogenous excitatory amino acids cannot bind [(+)-5-methyl-10, 11-dihydro-5H-dibenzo(a,d)]cyclohept-5,10-imine maleate] ([³H]MK-801). However, they do so upon the restoration of excitatory amino acid agonists such asl-glutamate. [³H]MK-801 provides a molecular probe which is specific for a binding site located within the ionophore of the N-methyl-d-aspartate-type excitatory amino acid receptor. [³H]MK-801 does not bind to non-N-methyl-d-aspartate excitatory amino acid receptors. Exploiting [³H]MK-801 binding as a quantitative measure of agonist activity with respect to ability of inducing the open channel conformation, the present study demonstrates thatl-homocysteate is an agonist almost equivalent tol-glutamate in terms of efficacy (maximal N-methyl-d-aspartate response) as well as potency (ec₅₀). The effect ofl-homocysteate was dose-dependent, stereospecific (l-homocysteate >dl-homocysteate >d-homocysteate), suppressible by the N-methyl-d-aspartate-selective competitive antagonist (±)-3(2-carboxypiperazine-4-yl)propyl-1-phosphonate, and potentiated by the N-methyl-d-aspartate-selective “allosteric” modulator glycine. The demonstrated inactivity ofl-homocysteine (and virtually all naturally occurring, non-acidic amino acids) implies that the ω-sulphonic acid moiety is an acceptable substitute for the ω-carboxyl group for activating the N-methyl-d-aspartate receptor. While the potency ofl-homocysteate at N-methyl-d-aspartate receptors was by a factor of only 1.6 smaller than that ofl-glutamate, the affinity ofl-homocysteate for kainate-type excitatory amino acid receptors was ≈ four-fold lower than that ofl-glutamate.

The present investigation thus corroborates and expands previous evidence suggesting thatl-homocysteate may represent an endogenous excitatory neurotransmitter that displays some preference for N-methyl-d-aspartate receptors.