ORIGINAL ARTICLES  CELLULAR AND MOLECULAR ADVANCES IN THE STUDY OF INFLAMMATION 

Minerva Biotecnologica 2004 June;16(2):109-18

Copyright © 2004 EDIZIONI MINERVA MEDICA

language: English

Structure-activity relationships around the KN-62, a potent antagonist of the P2X7receptor

Baraldi P. G. ^{1, 2}, Preti D. ¹, Pavani M. G. ¹, Bovero A. ¹, Iaconinoto A. ¹, Tabrizi M. A. ¹, Fruttarolo F. ¹, Di Virgilio F. ^{2, 3}, Romagnoli R. ¹

¹ Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy; ² Interdisciplinary Center for the Study of Inflammation (ICSI) University of Ferrara, Ferrara, Italy; ³ Section of General Pathology, Department of Diagnostic and Experimental Medicine, University of Ferrara, Ferrara, Italy

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 ­gave 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 mono­cyte-­derived ­human mac­ro­phag­es, a ­cell ­type ­well ­known for its ­high lev­el of expres­sion of ­this recep­tor.