QUANTIFICATION OF SCH-39166, A NOVEL SELECTIVE D1 DOPAMINE RECEPTOR ANTAGONIST, IN RAT-BRAIN AND BLOOD
QUANTIFICATION OF SCH-39166, A NOVEL SELECTIVE D1 DOPAMINE RECEPTOR ANTAGONIST, IN RAT-BRAIN AND BLOOD
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DOI：
10.1007/bf02244814
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发表时间：
1992-04-01
影响因子：
3.4
通讯作者：
SYVALAHTI, E
中科院分区：
文献类型：
--
作者：
HIETALA, J;SEPPALA, T;SYVALAHTI, E
开发了一种气相色谱方法，用于测量大鼠脑和血浆中新型 DI 拮抗剂 SCH 39166 [(-)-trans-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5-H-苯并[d]萘并(2,1-6)氮杂卓]的浓度。该方法适用于 SCH 39166 两种皮下剂量（0.25 mg/kg 和 2.5 mg/kg）的描述性药代动力学。为了进行比较，还测量了血浆和脑中“原型”D1 拮抗剂 SCH 23390（0.25 mg/kg，SC）[R-(+)-氯-2,3,4,5-四氢-3-甲基-5-苯基-1-H-3-苯并氮杂]的浓度。 SCH 23390（0.25 mg/kg，SC）在血浆中的消除半衰期非常短，约为 30 分钟，并且从纹状体和皮质中消失的速度稍慢。然而，SCH 39166（0.25 和 2.5 mg/kg，SC）在血浆和脑中的消除半衰期较长，约为 1.5-2.5 小时。有趣的是，与 0.25 mg/kg 剂量相比，2.5 mg/kg 剂量的 SCH 39166 在血浆和脑中的最大浓度仅增加了 2 至 5 倍。其原因尚不清楚。还评估了这两种剂量的 SCH 39166 在棒测试中诱发强直性昏厥的能力。结果发现，与 SCH 23390 不同，这两种剂量的 SCH 39166 不会导致强直性癫痫。总之，在设计这种新型选择性 D1 拮抗剂的实验时，SCH 39166 在大鼠中的这些药代动力学特征应该很有用。此外，SCH 39166 较长的消除半衰期使其成为 D1 受体拮抗剂与经典及非典型抗精神病药药效比较中更有用的探针。
A gas chromatographic method for measuring concentrations of a novel DI antagonist SCH 39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5-H-benzo[d]naphto(2,1-6)azepine] in rat brain and plasma was developed. The method was applied to descriptive pharmacokinetics of two subcutaneous doses of SCH 39166 (0.25 mg/kg and 2.5 mg/kg). For comparison, concentrations of the "prototype" D1 antagonist SCH 23390 (0.25 mg/kg, SC) [R-(+)-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine] were also measured in plasma and brain. SCH 23390 (0.25 mg/kg, SC) had a very short elimination half-life of about 30 min in plasma, and disappeared in a slightly slower manner from striatum and cortex. SCH 39166 (0.25 and 2.5 mg/kg, SC), however, had a longer elimination half-life of about 1.5-2.5 h in plasma and brain. Interestingly, the 2.5 mg/kg dose of SCH 39166 produced only two-to five-fold increases in maximum concentrations in plasma and brain compared to the 0.25 mg/kg dose. The reason for this is not clear. The ability of these two doses of SCH 39166 to induce catalepsy in the bar test was also evaluated. It was found that SCH 39166 in these two doses, unlike SCH 23390, was not cataleptic. In conclusion, these pharmacokinetic features of SCH 39166 in the rat should be useful when designing experiments with this novel selective D1 antagonist. Furthermore, the longer elimination half-life of SCH 39166 makes it a more useful probe in pharmacodynamic comparisons of D1 receptor antagonists and classical as well as atypical neuroleptics.