Synthesis, biological activity and molecular modeling studies of 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally constrained analogues of KN62, a potent antagonist of the P2X7-receptor containing a tyrosine moiety.

A new series of ring constrained analogues of the P2X7 receptor antagonist KN62 (1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, CAS 127191-97-3) containing the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid core with S configuration in position 3 was synthesised and their antagonist activities were tested on human macrophage cells. While KN62 is a potent antagonist of the P2X7 receptor, these novel compounds are weak antagonists of the purinergic P2X7 receptor and only one compound (5) showed appreciable activity as P2X7 antagonist, which was 30 times weaker than that reported for KN62. Along with compound 5, the derivatives 11 and 25 were the most active inhibitors in this synthesised series. A molecular modeling study confirmed that an extended rather than folded conformation seems to be crucial for the antagonistic activity at the P2X7 receptor.