TY - JOUR

T1 - Blockade of NMDA receptor channels by 9-aminoacridine and its derivatives

AU - Barygin, Oleg I.

AU - Gmiro, Valery E.

AU - Kim, Kira Kh

AU - Magazanik, Lev G.

AU - Tikhonov, Denis B.

N1 - Funding Information: This work is supported by RFBR grants 0804-00326 and 0704-00617, Russian Scientific School grant 4821.2008.4, and by grant of RAS program “Molecular and Cell Biology”.

PY - 2009/2/13

Y1 - 2009/2/13

N2 - 9-Aminoacridine is known as "foot-in-the-door" NMDA receptor channel blocker because its binding prevents channel closure. Structural determinants of this mechanism of block were studied using a series of 9-aminoacridine derivatives. Experiments were performed on native NMDA receptors of hippocampal pyramidal neurons, isolated from rat brain slices. The use-dependence of block and kinetics of recovery from block were used to characterize mechanism of block produced by the compounds. Modifications, which preserve the flat structure of the tricyclic 9-aminoacridine moiety, affect blocking activity and kinetics but not the foot-in-the-door mechanism. On the contrary, disruption of the flat structure changes the mechanism of block to trapping. It is concluded that flat aromatic structure is one of the critical determinants of the action mechanism of 9-aminoacridine.

AB - 9-Aminoacridine is known as "foot-in-the-door" NMDA receptor channel blocker because its binding prevents channel closure. Structural determinants of this mechanism of block were studied using a series of 9-aminoacridine derivatives. Experiments were performed on native NMDA receptors of hippocampal pyramidal neurons, isolated from rat brain slices. The use-dependence of block and kinetics of recovery from block were used to characterize mechanism of block produced by the compounds. Modifications, which preserve the flat structure of the tricyclic 9-aminoacridine moiety, affect blocking activity and kinetics but not the foot-in-the-door mechanism. On the contrary, disruption of the flat structure changes the mechanism of block to trapping. It is concluded that flat aromatic structure is one of the critical determinants of the action mechanism of 9-aminoacridine.

KW - Ion channel blockade

KW - NMDA receptors

KW - Structure-function relationships

UR - http://www.scopus.com/inward/record.url?scp=58249134996&partnerID=8YFLogxK

U2 - 10.1016/j.neulet.2008.12.036

DO - 10.1016/j.neulet.2008.12.036

M3 - Article

C2 - 19111901

AN - SCOPUS:58249134996

VL - 451

SP - 29

EP - 33

JO - Neuroscience Letters

JF - Neuroscience Letters

SN - 0304-3940

IS - 1

ER -