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

  • Bioorg Med Chem Lett. 2008 Jan 15;18(2):571-5. doi: 10.1016/j.bmcl.2007.11.077.
Ga Eun Lee  1 ,  Bhalchandra V Joshi ,  Wangzhong Chen ,  Lak Shin Jeong ,  Hyung Ryong Moon ,  Kenneth A Jacobson ,  Yong-Chul Kim
Affiliations
  • 1. Department of Life Science, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Republic of Korea.
PMID: 18078749 DOI: 10.1016/j.bmcl.2007.11.077
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.