Synthesis of Dihydrofuroaporphine Derivatives: Identification of a Potent and Selective Serotonin 5-HT1A Receptor Agonist
Synthesis of Dihydrofuroaporphine Derivatives: Identification of a Potent and Selective Serotonin 5-HT1A Receptor Agonist
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二氢呋喃阿朴啡衍生物的合成：强效选择性血清素 5-HT1A 受体激动剂的鉴定
DOI：
10.1021/jm9015763
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发表时间：
2010-02-11
影响因子：
7.3
通讯作者：
Zhang, Ao
中科院分区：
文献类型：
--
作者：
Liu, Zhili;Zhang, Hai;Zhang, Ao
合成了一系列新的阿朴啡类似物并进行了药理学评价。 11-烯丙氧基-(17)、11-炔丙氧基-(20) 和二氢呋喃-(19) 阿朴啡对 5-HT1A 受体表现出最高的亲和力，K-i 值分别为 12.0、14.0 和 6.7 nM。发现阿朴啡 19 非对映异构体混合物的高结合潜力存在于顺式非对映异构体 (cis-19) 中。对5-HT1A受体的[S-35]GTPγS功能测定表明，阿朴啡17和20是部分激动剂，而trans-19是高效完全拮抗剂，cis-19是完全激动剂。 cis-19对5-HT1A受体的激动特性在体外和体内得到进一步证实。该化合物可能可用作焦虑症的潜在治疗方法。
A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT1A receptor with K-i values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [S-35]GTP gamma S function assays on 5-HT1A receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT1A receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.