ALAPROCLATE ACTS AS A POTENT, REVERSIBLE AND NONCOMPETITIVE ANTAGONIST OF THE NMDA RECEPTOR-COUPLED ION FLOW

: WILKINSON A, COURTNEY M, WESTLINDDANIELSSON A, HALLNEMO G, AKERMAN KEO

Publisher: WILLIAMS & WILKINS

: 1994

: Journal of Pharmacology and Experimental Therapeutics

: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS

: J PHARMACOL EXP THER

: 271

: 3

: 1314

: 1319

: 6

: 0022-3565

We studied the effect of alaproclate [2-(4-chlorophenyl)-1,1-dimethyl 2-aminopropanoate] on the N-methyl-D-aspartate (NMDA)-induced changes in membrane potential and intracellular free Ca++ in cerebellar granule cells by using the fluorescent indicators DiBaC(4)(3) and fura-2, respectively. The NMDA-induced responses were blocked by the 5-hydroxytryptamine reuptake blocker alaproclate in a noncompetitive manner with an IC50 value of 0.3 mu M. The effect of alaproclate was stereoselective because the S-(-)-enantiomer was more potent than the R-(+)-enantiomer. The inhibitory response was rapidly reversed if alaproclate was removed by perfusion. The same was the case with the reversible noncompetitive NMDA receptor antagonists dextromethorphan, dextrorphan, amitriptyline and desipramine. The inhibition caused by the noncompetitive antagonist dizolcipine could not be reversed by perfusion. The glycine-sensitivity of the NMDA response was unaffected by alaproclate, and high concentrations of glycine were unable to reverse the inhibition by alaproclate. Alaproclate also did not affect the sensitivity of the responses to Mg++, The results suggest that alaproclate, which has previously been in clinical trials for depressive illness, acts as a reversible noncompetitive antagonist of the NMDA receptor.