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

Derivatives of phenylethylamine and tryptamine share structural features with the non-competitive N-methyl-D-aspartate (NMDA) receptor blockers phencyclidine, ketamine, and MK-801. Tryptamine and phenylethylamine inhibited the specific binding of [(3)H]MK-801 to rat hippocampal membranes with IC(50)'s 190 and 905 microM, respectively. The corresponding amino acids phenylalanine and tryptophan were inactive, their methyl esters, however, were slightly more potent than the amines. The methyl ester of the naturally occurring L-tryptophan was 12 times more potent than the methyl ester of the D-isomer, whereas the corresponding isomers derived from phenylalanine exhibited no stereoselectivity. The potency of tryptamine was increased by substitutions as, e.g. in 5-methyltryptamine (IC(50) 12 microM) and tryptophan octylester (IC(50) 5.2 microM). Compounds formed in vivo from L-tryptophan and a lipophilic counterpart may function as endogenous non-competitive NMDA receptor blockers.