L-homocysteate stimulates [3H]MK-801 binding to the phencyclidine recognition site and is thus an agonist for the N-methyl-D-aspartate-operated cation channel.

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 as L-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 that L-homocysteate is an agonist almost equivalent to L-glutamate in terms of efficacy (maximal N-methyl-D-aspartate response) as well as potency (EC50). The effect of L-homocysteate was dose-dependent, stereospecific (L-homocysteate greater than DL-homocysteate greater than D-homocysteate), suppressible by the N-methyl-D-aspartate-selective competitive antagonist (+/-)-3(2-carboxy-piperazine-4-yl)propyl-l-phosphonate, and potentiated by the N-methyl-D-aspartate-selective "allosteric" modulator glycine. The demonstrated inactivity of L-homocysteine (and virtually all naturally occurring, non-acidic amino acids) implies that the omega-sulphonic acid moiety is an acceptable substitute for the omega carboxyl group for activating the N-methyl-D-aspartate receptor. While the potency of L-homocysteate at N-methyl-D-aspartate receptors was by a factor of only 1.6 smaller than that of L-glutamate, the affinity of L-homocysteate for kainate-type excitatory amino acid receptors was approximately four-fold lower than that of L-glutamate.(ABSTRACT TRUNCATED AT 250 WORDS)