Shah J H, Kline R H, Geter-Douglass B, Izenwasser S, Witkin J M, Newman A H
Division of Intramural Research, National Institutes of Health, National Institute on Drug Abuse, Baltimore, Maryland 21224, USA.
J Med Chem. 1996 Aug 16;39(17):3423-8. doi: 10.1021/jm960143p.
Neurochemical studies and structure-activity relationships of dopamine D1 receptor ligands suggest that their intrinsic activity may depend on the conformational state or binding site at which they interact on the receptor protein. Important differences in the modes of binding of these ligands may confer their agonist, partial agonist, or antagonist properties. In an effort to develop novel dopamine D1 antagonists and investigate the D1 antagonist pharmacophore, a series of (+/-)-(N-alkylamino)benzazepines were prepared in which (+/-)-7-chloro-8-hydroxy-3-[6-(N,N-dimethylamino)hexyl]-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine (1) demonstrated the highest binding affinity (Ki = 49.3 nM) and selectivity to dopamine D1 receptors. This compound inhibited dopamine-stimulated adenylyl cyclase, in rat caudate, confirming a D1 receptor antagonist profile. From this initial series of N-alkylamino-substituted benzazepines, structure-activity relationships suggested that the terminal amino function was necessary for optimal binding affinity and selectivity at D1 vs D2 sites. Further, addition of this side chain to the D1 agonist pharmacophore (e.g., 7,8-dihydroxy-3-[4-(N,N-dimethylamino)butyl]-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine) greatly decreased binding affinity at D1 receptors. These data suggested that a binding domain that may be unique to the D1 antagonists may have been identified. In an attempt to exploit an apparent amine-accepting binding domain on the D1 receptor, a series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepine analogs was designed and prepared, as D1 antagonists. In this series, (+/-)-7-chloro-8-hydroxy-3-[4'-(N,N-dimethylamino)cinnamyl]-1-phenyl-2,3,4,5 -tetrahydro-1H-3-benzazepine (6a) showed the highest binding affinity (Ki = 60.3 nM) for dopamine D1 receptors. Compound 6a was a potent dopamine D1 antagonist as evidenced by its ability to block dopamine-stimulated adenylyl cyclase activity in rat caudate (predicted Ki value = 18.4 nM). Molecular modeling studies demonstrated that the most potent and selective dopamine D1 antagonists, in both series, contained terminal amino groups 8-9 A away from the 3-position benzazepine nitrogen. Compounds that lacked a terminal amine function or where this moiety was less than 7 A away from the benzazepine nitrogen demonstrated significantly lower binding affinities. Therefore, this series of (+/-)-3-[4'-(N,N-dimethylamino)cinnamyl]benzazepines also appears to be identifying an amine-accepting binding domain on the dopamine D1 receptor protein that may be further explored for the development of novel dopamine D1 antagonists.
多巴胺D1受体配体的神经化学研究及构效关系表明，它们的内在活性可能取决于其在受体蛋白上相互作用的构象状态或结合位点。这些配体结合模式的重要差异可能赋予它们激动剂、部分激动剂或拮抗剂的特性。为了开发新型多巴胺D1拮抗剂并研究D1拮抗剂药效团，制备了一系列（±）-（N-烷基氨基）苯并氮杂卓，其中（±）-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（1）对多巴胺D1受体表现出最高的结合亲和力（Ki = 49.3 nM）和选择性。该化合物在大鼠尾状核中抑制多巴胺刺激的腺苷酸环化酶，证实了其D1受体拮抗剂的特性。从这一系列最初的N-烷基氨基取代的苯并氮杂卓中，构效关系表明末端氨基官能团对于在D1与D2位点的最佳结合亲和力和选择性是必需的。此外，将该侧链添加到D1激动剂药效团（例如，7,8-二羟基-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）上会大大降低其在D1受体上的结合亲和力。这些数据表明可能已经鉴定出一个可能是D1拮抗剂特有的结合结构域。为了利用D1受体上一个明显的胺接受结合结构域，设计并制备了一系列（±）-3-[4'-（N，N-二甲基氨基）肉桂基]苯并氮杂卓类似物作为D1拮抗剂。在该系列中，（±）-7-氯-8-羟基-3-[4'-（N，N-二甲基氨基）肉桂基]-1-苯基-2,3,4,5-四氢-1H-3-苯并氮杂卓（6a）对多巴胺D1受体表现出最高的结合亲和力（Ki = 60.3 nM）。化合物6a是一种有效的多巴胺D1拮抗剂，其在大鼠尾状核中阻断多巴胺刺激的腺苷酸环化酶活性的能力证明了这一点（预测的Ki值 = 18.4 nM）。分子模拟研究表明，在这两个系列中，最有效和选择性最高的多巴胺D1拮抗剂都含有距离3-位苯并氮杂卓氮原子8-9 Å的末端氨基。缺乏末端胺官能团或该部分距离苯并氮杂卓氮原子小于7 Å的化合物表现出明显较低的结合亲和力。因此，这一系列（±）-3-[4'-（N，N-二甲基氨基）肉桂基]苯并氮杂卓似乎也在鉴定多巴胺D1受体蛋白上的一个胺接受结合结构域，可进一步探索用于开发新型多巴胺D1拮抗剂。
