Abstract

An increasing body of evidence supports the hypothesis that diminished function of N-methyl-d-aspartate (NMDA) receptors and the associated increase in glutamate release and overstimulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors are critical elements of the pathophysiology of schizophrenia. Here, we describe a halogenated derivative of the aromatic amino acid l-phenylalanine that 1) activates NMDA receptors, 2) depresses presynaptic glutamate release, and 3) blocks AMPA/kainate receptors. The experiments were conducted in rat cerebrocortical cultured neurons by using the patch-clamp technique. 3,5-Dibromo-l-phenylalanine (3,5-DBr-l-Phe) augmented NMDA miniature excitatory postsynaptic currents (mEPSCs) and activated the steady-state current, effects that were eliminated by NMDA receptor antagonists dl-2-amino-5-phosphonopentanoic acid and MK-801 (dizocilpine maleate; 5H-dibenzo[a,d]cyclohepten-5,10-imine). 3,5-DBr-l-Phe was a partial agonist at the glutamate-binding site of NMDA receptors with an EC₅₀ of 331.6 ± 78.6 μM and with an efficacy of 30.5 ± 4.7% compared with NMDA. 3,5-DBr-l-Phe depressed both amplitude and frequency of AMPA/kainate mEPSCs. The IC₅₀ of 3,5-DBr-l-Phe to inhibit AMPA/kainate mEPSC frequency was 29.4 ± 4.3 μM. 3,5-DBr-l-Phe significantly decreased paired pulse depression of AMPA/kainate EPSCs and attenuated current activated by AMPA with higher efficacy at lower concentration of AMPA. 3,5-DBr-l-Phe neither affected GABA miniature inhibitory postsynaptic currents nor elicited action potentials. By enhancing NMDA receptor function, reducing glutamate release and blocking AMPA/kainate receptors 3,5-DBr-l-Phe represents a new type of polyvalent modulator of glutamatergic synaptic transmission with potential therapeutic applications.