Abstract
Because N-Methyl-D-aspartate (NMDA) type glutamate receptor has been considered to be involved in the higher brain functions such as learning and memory, facilitating effects of glycine, D-serine and D-alanine on the NMDA receptor-mediated transmission are expected to ameliorate a variety of neuropsychiatric disorders. However, the low ability of these polar amino acids to cross through the blood-brain barrier (BBB) would be a serious disadvantage in their systemic administration for the clinical application. Indeed, extremely large doses of glycine and D-serine have been reported to be required to attenuate schizophrenic symptoms. To overcome this disadvantage through increasing the fat solubility of D-serine, the authors designed and synthesized N-acyl D-serine and evaluated its permeability of the BBB by testing in the rat the effects of the N-acyl compound on abnormal behavior induced by a potent NMDA antagonist chizophrenomimetic, phencyclidine, which is thought to be a model of schizophrenia. Intraperitoneal injection of the N-acyl D-serine attenuated the phencyclidine-induced abnormal behavior and this attenuation was diminished by intraventricular application of a selective antagonist for the glycine modulatory site of the NMDA receptor at which D-serine acts as a selective agonist. These data support the BBB permeability of the acyl D-serine and suggest that certain fat soluble amino acids could be useful for the treatment of neuropsychiatric disorders.
