The effects of β-amyloid protein 1–40 (β AP 1–40), substance P (SP), and the amidated and carboxylic acid C-terminated forms of the SP homologous β AP fragment 25–35 (β AP 25–35-NH2 and β AP 25–35-COOH) were studied on [3H]MK-801 binding to the rat brain NMDA receptor cation channel. All peptides gave dose-dependent enhancements of [3H]MK-801 binding stimulated by low glycine. β AP 25–35-COOH, but not β AP 25–35-NH2 produced an inhibition of [3H]MK-801 binding stimulated by high glycine in the presence of either low or high glutamate. Low glutamate-stimulated [3H]MK-801 binding was also inhibited by SP but not by β AP 1–40. It is concluded that β AP related peptides exert differential effects on the NMDA receptor complex at the glycine and possibly also the glutamate recognition sites.