Structure-activity relationships around the KN-62, a potent antagonist of the P2X7receptor

摘要

Two different series of analogues of KN-62, a potent antagonist of the P2X7 receptor on human lymphocytes, are reported in this review article. The first series was represented by ring constrained analogues of KN-62, containing the l,2,3,4-tetrahydroisoquinoline-3-carbox-ylic acid core with S configuration in position 3- "While KN-62 is a potent antagonist of the P2X_7 receptor, this first series of compounds are weak antagonists of the purinergic P2X_7 receptor and only one compound (le) showed appreciable activity as P2X_7 antagonist, which was 30 times weaker than that reported for KN-62. The second series of compounds was characterised by the presence of different phenyl-substituted piperazine moieties. KN-62 was characterized by the presence of a phenyl-piperazine moiety and the nature and the position of substituents on the phenyl ring tethered to the piperazine seemed to exert a fundamental influence on the biological activity. In particular, the presence of a fluorine in para position gave the more potent compound (4c), while the same atom in ortho position reduces potency by 3-fold. Antagonistic activity of both these series of KN-62 derivatives was tested on monocyte-derived human macrophages, a cell type well known for its high level of expression of this receptor.