Tryptamine derivatives as non-competitive N-methyl-D-aspartate receptor blockers: studies using [H-3]MK-801 binding in rat hippocampal membranes

Derivatives of phenylethylamine and tryptamine share structural features wi th the non-competitive N-methyl-D-aspartate (NMDA) receptor blockers phency clidine, ketamine, and MK-801. Tryptamine and phenylethylamine inhibited th e specific binding of [H-3]MK-801 to rat hippocampal membranes with IC50'S 190 and 905 muM, respectively. The corresponding amino acids phenylalanine and tryptophan were inactive, their methyl esters, however, were slightly m ore potent than the amines. The methyl ester of the naturally occurring L-t ryptophan was 12 times more potent than the methyl ester of the D-isomer, w hereas the corresponding isomers derived from phenylalanine exhibited no st ereoselectivity. The potency of tryptamine was increased by substitutions a s, e.g, in 5-methyltryptamine (IC50 12 muM) and tryptophan octylester (IC50 5.2 muM). Compounds formed in vivo from L-tryptophan and a lipophilic coun terpart may function as endogenous non-competitive NMDA receptor blockers. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.