'Click' D(1) receptor agonists with a 5-HT(1A) receptor pharmacophore producing D(2) receptor activity.
'Click' D(1) receptor agonists with a 5-HT(1A) receptor pharmacophore producing D(2) receptor activity.
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DOI：
10.1016/j.bmc.2009.06.019
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发表时间：
2009-07
影响因子：
3.5
通讯作者：
Jing Zhang;Hai Zhang;Wenxian Cai;Leiping Yu;Xuechu Zhen;A. Zhang
中科院分区：
文献类型：
--
作者：
Jing Zhang;Hai Zhang;Wenxian Cai;Leiping Yu;Xuechu Zhen;A. Zhang
通过Click反应将D1受体激动剂药效团与5-HT 1A受体药效团结合，合成了一系列新的含芳基哌嗪基N3取代基的1-芳基-3-苯并氮杂卓衍生物。有趣的是，这些化合物通常对D1受体没有良好的结合亲和力，但大多数化合物对D2和5-HT 1A受体都有效。含有1-间甲苯基-苯并氮杂卓骨架和2-甲氧基苯基哌嗪核心的化合物8h对所有测试的受体均显示出良好的亲和力，对D1、D2和5-HT 1A受体的Ki值分别为144、80和133 nM。与8h不同，三唑基团形成的化合物13对D2受体表现出最高的亲和力，Ki值为19 nM。该化合物对5-HT 1A（Ki，105 nM）和D1（Ki，551 nM）受体也显示出中等亲和力。功能测定表明，化合物13和8h都是D1和D2受体的拮抗剂，而观察到对5-HT 1A受体的完全激动活性。化合物13是一种高效的D2受体拮抗剂和5-HT 1A受体激动剂。
A series of new 1-aryl-3-benzazepine derivatives containing an arylpiperazinyl function as the N3 substituent were synthesized by combining a D1receptor agonistic pharmacophore and a 5-HT1Areceptor pharmacophore through Click reaction. Interestingly, these compounds generally do not have good binding affinity at the D1receptor, but most compounds are potent at both D2and 5-HT1Areceptors. Compound 8h, containing 1-m-tolyl-benzazepine scaffold and 2-methoxyphenylpiperazine core, displayed good affinity at all tested receptors, with Kivalues of 144, 80, and 133nM, for the D1, D2, and 5-HT1Areceptors, respectively. Compound 13 with the triazole moiety formed differently from that in 8h showed the highest affinity at the D2receptor with Kivalue of 19nM. This compound also showed moderate affinity at the 5-HT1A(Ki, 105nM), and D1(Ki, 551nM) receptors. Functional assays indicated that both compounds 13 and 8h are antagonists at D1and D2receptors, whereas full agonistic activity at the 5-HT1Areceptor was observed. In agreement with the binding affinity, compound 13 is a high efficacy D2antagonist and 5-HT1Aagonist.