Synthesis of dihydrofuroaporphine derivatives: Identification of a potent and selective serotonin 5-HT1A receptor agonist

Zhili Liu; Hai Zhang; Na Ye; Jing Zhang; Qian Qian Wu; Peihua Sun; Nyong Li; Xuechu Zhen; Ao Zhang

doi:10.1021/jm9015763

Synthesis of dihydrofuroaporphine derivatives: Identification of a potent and selective serotonin 5-HT_1A receptor agonist

Zhili Liu, Hai Zhang, Na Ye, Jing Zhang, Qian Qian Wu, Peihua Sun, Nyong Li, Xuechu Zhen, Ao Zhang

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

Abstract

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-HT_1A 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). [³⁵S]GTPγS function assays on 5-HT_1A 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-HT_1A receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.

Original language	English (US)
Pages (from-to)	1319-1328
Number of pages	10
Journal	Journal of medicinal chemistry
Volume	53
Issue number	3
DOIs	https://doi.org/10.1021/jm9015763
State	Published - 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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title = "Synthesis of dihydrofuroaporphine derivatives: Identification of a potent and selective serotonin 5-HT1A receptor agonist",

abstract = "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 Ki 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). [35S]GTPγS 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.",

author = "Zhili Liu and Hai Zhang and Na Ye and Jing Zhang and Wu, \{Qian Qian\} and Peihua Sun and Nyong Li and Xuechu Zhen and Ao Zhang",

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doi = "10.1021/jm9015763",

language = "English (US)",

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TY - JOUR

T1 - Synthesis of dihydrofuroaporphine derivatives

T2 - Identification of a potent and selective serotonin 5-HT1A receptor agonist

AU - Liu, Zhili

AU - Zhang, Hai

AU - Ye, Na

AU - Zhang, Jing

AU - Wu, Qian Qian

AU - Sun, Peihua

AU - Li, Nyong

AU - Zhen, Xuechu

AU - Zhang, Ao

PY - 2010

Y1 - 2010

N2 - 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 Ki 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). [35S]GTPγS 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.

AB - 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 Ki 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). [35S]GTPγS 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.

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JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 3

ER -

Synthesis of dihydrofuroaporphine derivatives: Identification of a potent and selective serotonin 5-HT_1A receptor agonist

Abstract

ASJC Scopus subject areas

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