Affinity of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives to the ion channel binding site of the NMDA receptor complex.

A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The (S)-configured tetrahydroisoquinoline derivative (S)-4 e x HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K(i)-value of 0.0374 microM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding (R)-enantiomer (R)-4 e x HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.