SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems.
SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems.
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发表时间：
1983-08
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通讯作者：
L. Iorio;A. Barnett;F. Leitz;V. Houser;C. Korduba
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作者：
L. Iorio;A. Barnett;F. Leitz;V. Houser;C. Korduba
SCH 23390[R-(+)-8-chloro-2，3，4，5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol)具有与标准抗精神病药物相似的药理作用，包括选择性抑制大鼠和松鼠的条件性回避反应，阻断阿朴吗啡诱导的大鼠刻板行为，阻断甲基苯丙胺诱导的聚集小鼠的致死性。在这些测试中，在有效剂量下，没有观察到总体行为、神经或自主功能的变化。与测试的标准相比，SCH 23390阻断多巴胺刺激的腺苷环化酶的浓度(IC_(50)=0.01微米)比阻断螺环酮结合所需的浓度(IC_(50)=24微米)低约2000倍。这表明D1R具有特异性拮抗作用。SCH 23390不能引起高催乳素血症，被认为是D2受体效应，与这一假说是一致的。SCH 23390表现出较低的多巴胺周转增加，这表明对SCH 23390的阻断可能更针对突触后部位而不是突触前部位。在推测的突触后多巴胺位点中，SCH 23390具有选择性的其他证据包括它对阿朴吗啡引起的体温过低或呕吐缺乏影响。根据这些结果，推测SCH 23390是一种选择性的D_1受体拮抗剂。
SCH 23390 [R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) possesses pharmacologic effects similar to standard antipsychotics, including selective supression of conditioned avoidance responding in rats and squirrel monkeys, blockade of apomorphine-induced stereotypy in rats and blockade of methamphetamine-induced lethality in aggregated mice. At effective doses in these tests, no changes in gross behavior, neurological or autonomic function were observed. In contrast to the standards tested, SCH 23390 blocked dopamine-stimulated adenylate cyclase at concentrations (IC50 = 0.01 microM) about 2000 times lower than those needed to block spiperone binding (IC50 = 24 microM). This suggests specific D1-receptor antagonism. Inability of SCH 23390 to cause hyperprolactinemia, considered to be a D2-receptor effect, is consistent with this hypothesis. SCH 23390 showed lower increases in dopamine turnover suggesting that the blockade of SCH 23390 may be more specific for post- than presynaptic sites. Additional evidence for the selectivity of SCH 23390 among putative postsynaptic dopamine sites includes its lack of effect on apomorphine-induced hypothermia or emesis. Based on these results, it is postulated that SCH 23390 is a selective D1-receptor antagonist.