TY - JOUR
T1 - Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3- quinoxalinedione
T2 - A novel systemically active ionotropic glutamate receptor antagonist
AU - Woodward, R. M.
AU - Huettner, J. E.
AU - Tran, M.
AU - Guastella, J.
AU - Keana, J. F.W.
AU - Weber, E.
PY - 1995
Y1 - 1995
N2 - 5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (K(b) values) were 0.4 to 0.8 μM in oocytes and ~0.6 μM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 μM (1 μM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 μM and K(b) values for ACEA-1011 between 0.2 to 0.8 μM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. K(b) values were 4 to 9 μM in oocytes and 9 to 10 μM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was ~12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
AB - 5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (K(b) values) were 0.4 to 0.8 μM in oocytes and ~0.6 μM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 μM (1 μM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 μM and K(b) values for ACEA-1011 between 0.2 to 0.8 μM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. K(b) values were 4 to 9 μM in oocytes and 9 to 10 μM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was ~12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.
UR - http://www.scopus.com/inward/record.url?scp=0029549965&partnerID=8YFLogxK
M3 - Article
C2 - 8531083
AN - SCOPUS:0029549965
SN - 0022-3565
VL - 275
SP - 1209
EP - 1218
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -