Chipkin R E, Iorio L C, Coffin V L, McQuade R D, Berger J G, Barnett A
Research Division, Schering-Plough Corporation, Bloomfield, New Jersey.
J Pharmacol Exp Ther. 1988 Dec;247(3):1093-102.
SCH39166 [(-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl- 5H-benzo[d]naptho-(2,1-b)azepine] is a benzonaphthazepine that has been evaluated as a selective D1 dopamine receptor antagonist. In vitro, SCH39166 (Ki = 3.6 nM) inhibited the binding of [3H]SCH23390 (a D1 specific compound) and blocked dopamine-stimulated adenylate cyclase (Ki = 9.1 nM); in contrast the Ki for SCH39166 to displace [3H]spiperone (D2) was greater than 1 microM and its Ki vs. [3H]-ketanserin (5-hydroxytryptamine2) binding was greater than 300 nM. In vivo, SCH39166 inhibited both rat and squirrel monkey conditioned avoidance responding (minimal effective dose = 10 and 1.78 mg/kg p.o., respectively) and had a duration of at least 6 hr in both species. In addition, SCH39166 antagonized apomorphine-induced stereotypy in rats (minimal effective dose = 10 mg/kg p.o.). These in vivo actions of SCH39166 are similar to the activity of typical dopamine antagonists. However, in contrast to D2-selective antagonists, SCH39166 failed to increase plasma prolactin levels, did not block apomorphine-induced emesis in the dog and had minimal effects on the striatal levels of homovanillic acid or dihydroxyphenylacetic acid. Furthermore, although immobility was seen after p.o. administration of SCH39166 using the inclined screen test, the drug did not cause catalepsy at doses up to 10 times its minimal effective dose in the rat conditioned avoidance response test. Additionally, SCH39166 inhibited apomorphine-induced climbing at lower doses than it inhibited apomorphine-induced sniffing in mice. The results from these latter two tests suggest that SCH39166 may have a reduced liability to produce extrapyramidal side effects. Therefore, based on this profile of activity, SCH39166 is a selective D1 dopamine receptor antagonist both in vitro and in vivo. Additionally, because this compound is longer acting in the primate than previously available D1 antagonists, it has potential utility as a clinically useful drug.
SCH39166 [(-)-反式-6,7,7a,8,9,13b-六氢-3-氯-2-羟基-N-甲基-5H-苯并[d]萘并-(2,1-b)氮杂卓]是一种苯并萘氮杂卓，已被评估为选择性D1多巴胺受体拮抗剂。在体外，SCH39166（Ki = 3.6 nM）抑制[3H]SCH23390（一种D1特异性化合物）的结合并阻断多巴胺刺激的腺苷酸环化酶（Ki = 9.1 nM）；相比之下，SCH39166置换[3H]螺哌隆（D2）的Ki大于1 μM，其与[3H]-酮色林（5-羟色胺2）结合的Ki大于300 nM。在体内，SCH39166抑制大鼠和松鼠猴的条件性回避反应（最小有效剂量分别为10和1.78 mg/kg口服），并且在这两个物种中的作用持续时间至少为6小时。此外，SCH39166拮抗大鼠中阿扑吗啡诱导的刻板行为（最小有效剂量 = 10 mg/kg口服）。SCH39166的这些体内作用类似于典型多巴胺拮抗剂的活性。然而，与D2选择性拮抗剂相反，SCH39166未能增加血浆催乳素水平，未阻断狗中阿扑吗啡诱导的呕吐，并且对纹状体中高香草酸或二羟基苯乙酸水平的影响最小。此外，尽管在使用倾斜屏幕试验口服给予SCH39166后观察到不动，但在大鼠条件性回避反应试验中，该药物在高达其最小有效剂量10倍的剂量下未引起僵住。另外，在小鼠中，SCH39166在比抑制阿扑吗啡诱导的嗅探更低的剂量下抑制阿扑吗啡诱导的攀爬。后两项试验的结果表明，SCH39166产生锥体外系副作用的可能性可能降低。因此，基于这种活性特征，SCH39166在体外和体内都是选择性D1多巴胺受体拮抗剂。此外，由于该化合物在灵长类动物中的作用时间比以前可用的D1拮抗剂更长，它具有作为临床有用药物的潜在用途。
