Cai S X, Kher S M, Zhou Z L, Ilyin V, Espitia S A, Tran M, Hawkinson J E, Woodward R M, Weber E, Keana J F
CoCensys Inc., Irvine, California 92618, USA.
J Med Chem. 1997 Feb 28;40(5):730-8. doi: 10.1021/jm960654b.
We report on a series of alkyl- and alkoxy-substituted 1,4-dihydroquinoxaline-2,3-diones (QXs), prepared as a continuation of our structure-activity relationship (SAR) study of QXs as antagonists for the glycine site of the N-methyl-D-aspartate (NMDA) receptor. The in vitro potency of these antagonists was determined by displacement of the glycine site radioligand [3H]-5,7-dichlorokynurenic acid ([3H]DCKA) in rat brain cortical membranes. In general, methyl is a good replacement for chloro or bromo in the 6-position, and alkoxy-substituted QXs have lower potencies than alkyl- or halogen-substituted QXs. Ethyl-substituted QXs are generally less potent than methyl-substituted QXs, especially in the 6-position of 5,6,7-trisubstituted QXs. Fusion of a ring system at the 6,7-positions results in QXs with low potency. Several methyl-substituted QXs are potent glycine site antagonists that have surprisingly high in vivo activity in the maximal electroshock (MES) test in mice. Among these, 7-chloro-6-methyl-5-nitro QX (14g) (IC50 = 5 nM) and 7-bromo-6-methyl-5-nitro QX (14f) (IC50 = 9 nM) are comparable in potency to 6,7-dichloro-5-nitro QX (2) (ACEA 1021) as glycine site antagonists. QX 14g has an ED50 value of 1.2 mg/kg iv in the mouse MES assay. Interestingly, alkyl QXs with log P values of 0.5 or less tend to be more bioavailable than QXs with higher log P values. QX 14g has 440-fold selectivity for NMDA vs alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as determined electrophysiologically under steady-state conditions in oocytes expressing rat cerebral cortex poly(A)+ RNA. Overall, 14g was found to have the best combination of in vitro and in vivo potency of all the compounds tested in this and previous studies on the QX series.
我们报道了一系列烷基和烷氧基取代的1,4 - 二氢喹喔啉 - 2,3 - 二酮（QXs），这是我们作为N - 甲基 - D - 天冬氨酸（NMDA）受体甘氨酸位点拮抗剂的QXs构效关系（SAR）研究的延续。这些拮抗剂的体外效力通过大鼠脑皮质膜中甘氨酸位点放射性配体[³H] - 5,7 - 二氯犬尿氨酸（[³H]DCKA）的置换来确定。一般来说，甲基是6位氯或溴的良好替代物，烷氧基取代的QXs效力低于烷基或卤素取代的QXs。乙基取代的QXs通常比甲基取代的QXs效力低，特别是在5,6,7 - 三取代QXs的6位。在6,7位稠合环系会导致QXs效力较低。几种甲基取代的QXs是有效的甘氨酸位点拮抗剂，在小鼠最大电休克（MES）试验中具有令人惊讶的高体内活性。其中，7 - 氯 - 6 - 甲基 - 5 - 硝基QX（14g）（IC50 = 5 nM）和7 - 溴 - 6 - 甲基 - 5 - 硝基QX（14f）（IC50 = 9 nM）作为甘氨酸位点拮抗剂，效力与6,7 - 二氯 - 5 - 硝基QX（2）（ACEA 1021）相当。在小鼠MES试验中，QX 14g静脉注射的ED50值为1.2 mg/kg。有趣的是，log P值为0.5或更低的烷基QXs往往比log P值更高的QXs具有更高生物利用度。如在表达大鼠大脑皮质多聚腺苷酸（poly(A)+）RNA的卵母细胞中在稳态条件下通过电生理学测定，QX 14g对NMDA与α - 氨基 - 3 - 羟基 - 5 - 甲基 - 4 - 异恶唑丙酸（AMPA）受体的选择性为440倍。总体而言，在本研究以及之前关于QX系列的研究中测试的所有化合物中，发现14g具有最佳的体外和体内效力组合。
