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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


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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.

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