Shah J H, Izenwasser S, Geter-Douglass B, Witkin J M, Newman A H
Psychobiology Section, National Institutes of Health, National Institute on Drug Abuse-Division of Intramural Research, Baltimore, Maryland 21224, USA.
J Med Chem. 1995 Oct 13;38(21):4284-93. doi: 10.1021/jm00021a018.
(+/-)-(N-Alkylamino)benzazepine analogs were prepared as novel dopamine D1 receptor antagonists to further elucidate the role of these receptor subtypes in the pharmacology and toxicology of cocaine. In the first series of compounds, (+/-)-7-chloro-8-hydroxy-3- [6-(N,N-dimethylamino)-hexyl]-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepi ne (15) showed the highest affinity (Ki = 49.3 nM) and subtype-selectivity for dopamine D1 over dopamine D2, 5-HT2a, and 5-HT2c receptors. Compounds 7a [(+/-)-7-Chloro-8-hydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl- 2,3,4,5-tetrahydro-1H-3-benzazepine], 11 [(+/-)-7-chloro-8-hydroxy-3-[6-[(N,N-dimethylamino)hexyl]-1- phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-cyanoborane], and 15 were moderately potent dopamine D1 receptor antagonists as evidenced by their ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki values = 60, 34, and 21 nM, respectively). Compound 7a appears to be unique in that, despite its relatively potent inhibition of dopamine stimulated adenylyl cyclase, it demonstrated relatively weak binding affinity at the dopamine D1 receptors (Ki = 811 nM). Unlike previously reported N-alkylbenzazepines, where a significant loss in dopamine D1 receptor binding affinity was observed when successive increases in the alkyl side chain size at the benzazepine nitrogen were made, several of these novel N-alkylamino analogs demonstrated high-affinity binding with an optimal chain length of six carbons. This initial series of compounds appears to be identifying another binding domain on the dopamine D1 receptor protein that has not previously been characterized and that accepts an amino function. Further, these compounds may serve as templates for the design of peripherally active dopamine D1 receptor antagonists.
制备了（±）-（N-烷基氨基）苯并氮杂卓类似物作为新型多巴胺D1受体拮抗剂，以进一步阐明这些受体亚型在可卡因药理学和毒理学中的作用。在第一系列化合物中，（±）-7-氯-8-羟基-3-[6-（N，N-二甲基氨基）己基]-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓（15）对多巴胺D1受体表现出最高的亲和力（Ki = 49.3 nM）以及对多巴胺D2、5-HT2a和5-HT2c受体的亚型选择性。化合物7a [（±）-7-氯-8-羟基-3-[4-（N，N-二甲基氨基）丁基]-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓]、11 [（±）-7-氯-8-羟基-3-[6-（N，N-二甲基氨基）己基]-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓-氰基硼烷]和15是中等效力的多巴胺D1受体拮抗剂，这可通过它们阻断大鼠尾状核中多巴胺刺激的腺苷酸环化酶活性的能力得到证明（预测的Ki值分别为60、34和21 nM）。化合物7a似乎很独特，因为尽管它对多巴胺刺激的腺苷酸环化酶有相对较强的抑制作用，但它在多巴胺D1受体上表现出相对较弱的结合亲和力（Ki = 811 nM）。与先前报道的N-烷基苯并氮杂卓不同，在苯并氮杂卓氮原子处烷基侧链大小连续增加时，多巴胺D1受体结合亲和力会显著降低，而这些新型N-烷基氨基类似物中的几种表现出高亲和力结合，最佳链长为六个碳原子。这一初始系列化合物似乎正在确定多巴胺D1受体蛋白上另一个以前未被表征且接受氨基功能的结合域。此外，这些化合物可作为设计外周活性多巴胺D1受体拮抗剂的模板。
