SCH 39166, a novel dopamine D1 receptor antagonist: In vitro investigation of its glucuronidation and potential species differences
SCH 39166, a novel dopamine D1 receptor antagonist: In vitro investigation of its glucuronidation and potential species differences
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SCH 39166，一种新型多巴胺 D1 受体拮抗剂：其葡萄糖醛酸化和潜在物种差异的体外研究
DOI：
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发表时间：
1992
期刊：
影响因子：
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通讯作者：
A. Barnett
中科院分区：
文献类型：
--
作者：
C. Tedford;V. Ruperto;V. Coffin;Mary Cohen;M. Libonati;A. Barnett
SCH 39166 是一种新型苯并萘氮杂卓，是一种选择性多巴胺 D1 受体拮抗剂。它目前正在进行人体临床试验，可能用作抗精神病药物。迄今为止，尚未有研究描述 SCH 39166 的代谢。因此，本研究调查了来自啮齿动物和松鼠猴肝微粒体的 SCH 39166 可能的体外葡萄糖醛酸化。与经典的 D1 拮抗剂 SCH 23390 进行了比较，SCH 23390 是一种苯并氮杂卓，在大鼠体内进行了广泛的葡萄糖醛酸苷化。此外，还将 SCH 39166 对大鼠和松鼠猴条件性回避范式 (CAR) 的剂量反应和作用持续时间与 SCH 23390 在这些物种中的剂量反应和作用持续时间进行了比较。结果表明 3H-SCH 39166 被大鼠和猴肝微粒体葡萄糖醛酸化。在大鼠肝微粒体研究中，SCH 39166 的葡萄糖醛酸化速率和对葡萄糖醛酸基转移酶的亲和力与 SCH 23390 相当。体内行为研究还表明，大鼠口服给药后，任一 D1 拮抗剂的剂量反应曲线或行为效应时程均无差异。相比之下，SCH 23390 在松鼠猴肝微粒体中的葡萄糖醛酸化速率比 SCH 39166 快 3-4 倍。此外，这些发现与松鼠猴的体内行为研究一致，其中 SCH 23390 的作用持续时间比 SCH 39166 短得多。 © 1992 wiley‐Liss, Inc.
SCH 39166 is a novel benzonaphthazepine that is a selective dopamine D1 receptor antagonist. It is currently undergoing clinical trials in humans for possible use as an antipsychotic medication. To date, no studies have been presented describing the metabolism of SCH 39166. Therefore, the present studies investigated the possible in vitro glucuronidation of SCH 39166 from both rodent and squirrel monkey liver microsomes. Comparisons were made with the classic D1 antagonist, SCH 23390, a benzazepine which undergoes extensive glucuron dation in the rat. Additionally, dose response and duration of action of SCH 39166 on the conditioned avoidance paradigm (CAR) in both rats and squirrel monkeys were compared to the dose response and duration of action of SCH 23390 in these species. Results demonstrated that 3H‐SCH 39166 was glucuronidated by both rat and monkey liver microsomes. In studies with rat liver microsomes, the rate of glucuronidation of SCH 39166 and the affinity for the glucuronosyltransferase enzyme were equivalent to those of SCH 23390. In vivo behavioral studies also indicated no differences in either the dose‐response curves or the time course of behavioral effects for either D1 antagonist after oral administration in the rat. In contrast, the rate of glucuronidation in squirrel monkey liver microsomes of SCH 23390 was 3–4 times faster than that of SCH 39166. Moreover, these findings consistent with in vivo behavioral studies in squirrel monkeys, in which the duration of action of SCH 23390 was much shorter than SCH 39166. © 1992 wiley‐Liss, Inc.
未接触过药物的猴子体内的多巴胺 D1 (SCH 23390) 和 D2（氟哌啶醇）拮抗剂。
影响因子：
3.4
作者：
Casey,DE
通讯作者：
Casey,DE