Structure-activity relationships around the KN-62, a potent antagonist of the P2X(7)receptor

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 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid core with S configuration in position 3. While KN-62 is a potent antagonist of the P2X7 receptor, this first series of compounds are weak antagonists of the purinergic P2X7 receptor and only one compound (1e) showed appreciable activity as P2X7 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 geve 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 monocytederived human macrophages, a cell type well known for its high level of expression of this receptor.