Synthesis and structure-activity relationship studies of tyrosine-based antagonists at the human P2X7 receptor |
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Authors: | Lee Ga Eun Joshi Bhalchandra V Chen Wangzhong Jeong Lak Shin Moon Hyung Ryong Jacobson Kenneth A Kim Yong-Chul |
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Institution: | Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea. |
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Abstract: | Analogues of the P2X(7) receptor antagonist KN-62, modified at the piperazine and arylsulfonyl groups, were synthesized and assayed at the human P2X(7) receptor for inhibition of BzATP-induced effects, that is, uptake of a fluorescent dye (ethidium bromide) in stably transfected HEK293 cells and IL-1beta 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 2,6-dimethyl groups corrected] in 9 enhanced antagonistic potency. |
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