Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity
Novel NMDA/glycine site antagonists attenuate cocaine-induced behavioral toxicity
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DOI：
10.1016/s0014-2999(97)81926-7
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发表时间：
1997-11-12
影响因子：
5
通讯作者：
Kanthasamy, AG
中科院分区：
文献类型：
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作者：
Matsumoto, RR;Brackett, RL;Kanthasamy, AG
在Swiss韦伯斯特小鼠中测试N-甲基-D-天冬氨酸（NMDA）/甘氨酸位点拮抗剂预防可卡因诱导的惊厥和致死性的能力。用新型NMDA/甘氨酸位点拮抗剂ACEA-1021（5-硝基-6，7-二氯-1，4-二氢-2，3-喹喔啉二酮）或ACEA-1328（5-硝基-6，7-二甲基-1，4-二氢-2，3-喹喔啉二酮）预处理小鼠可减轻可卡因诱导的惊厥;这些作用可被D-环丝氨酸拮抗。结构相关的NMDA/甘氨酸位点拮抗剂DCQX（6，7-二氯喹喔啉-2，3-二酮）和结构不相关的NMDA/甘氨酸位点部分激动剂HA-966（3-氨基-1-羟基-2-吡咯烷酮）也可减轻可卡因诱导的惊厥，HA-966的R（+）-异构体比S（-）-异构体更有效。相比之下，选择性α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体拮抗剂NBQX（1，2，3，4-四氢-6-硝基-2，3-二氧代-苯并[f]喹喔啉-7-磺酰胺）未能提供统计学显著的保护，尽管它与DCQX和ACEA化合物具有2，3-喹喔啉二酮结构。用ACEA-1021、ACEA-1328、DCQX或R（+）-HA-966预处理也减弱可卡因诱导的小鼠致死性。值得注意的是，在癫痫发作之前或之后立即用ACEA-1021进行后处理，防止了高达86%的接受致死剂量可卡因的小鼠死亡;用媒介物进行后处理导致所有小鼠死亡。结果表明靶向兴奋机制用于治疗可卡因过量的效用，并提供了一种新的基础结构，可以从中开发有效的药物疗法。(C)1997年Elsevier Science B.V.
N-Methyl-D-aspartate (NMDA)/glycine site antagonists were tested for their ability to prevent cocaine-induced convulsions and lethality in Swiss Webster mice. Pre-treatment of mice with the novel NMDA/glycine site antagonists ACEA-1021 (5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione) or ACEA-1328 (5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione) attenuated cocaine-induced convulsions; these effects were pharmacologically antagonized with D-cycloserine. The structurally-related NMDA/glycine site antagonist DCQX (6,7-dichloroquinoxaline-2,3-dione) and the structurally-unrelated NMDA/glycine site partial agonist HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) also attenuated cocaine-induced convulsions, with the R(+)-isomer of HA-966 being more effective than the S(-)-isomer. In contrast, the selective alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor antagonist, NBQX (1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide), failed to provide statistically significant protection although it shares the 2,3-quinoxalinedione structure of DCQX and the ACEA compounds. Pre-treatment with ACEA-1021, ACEA-1328, DCQX, or R(+)-HA-966 also attenuated cocaine-induced lethality in mice. Significantly, post-treatment with ACEA-1021, immediately prior to or after the onset of seizures, prevented death in up to 86% of mice receiving a lethal dose of cocaine; post-treatment with vehicle resulted in death of all mice, The results suggest the utility of targeting excitatory mechanisms for the treatment of cocaine overdose and offer a novel base structure from which effective pharmacotherapies can be developed. (C) 1997 Elsevier Science B.V.