Synthesis and in vitro activity of N-benzyl-1-(2,3-dichlorophenyl)-1H- tetrazol-5-amine P2X ₇ antagonists

Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X ₇ antagonists. These compounds were assayed for activity at both the human and rat P2X ₇ receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X ₇ receptors. Compounds 12 and 38 displayed hP2X ₇ pIC ₅₀s >7.8 with less than 2-fold difference in potency at the rP2X ₇.