Synthesis and structure–activity relationship studies of tyrosine-based antagonists at the human P2X7 receptor

Analogues of the P2X7 receptor antagonist KN-62, modified at the piperazine and arylsulfonyl groups, were synthesized and assayed at the human P2X7 receptor for inhibition of BzATP-induced effects, that is, uptake of a fluorescent dye (ethidium bromide) in stably transfected HEK293 cells and IL-1β release in differentiated THP-1 cells. Substitution of the arylsulfonyl moiety with a nitro group increased antagonistic potency relative to methyl substitution, such that compound 21 was slightly more potent than KN-62. Substitution with d-tyrosine in 36 and sterically bulky tyrosyl 3,5-dimethyl groups in 9 enhanced antagonistic potency.