Further SAR study on 11-O-substituted aporphine analogues: Identification of highly potent dopamine D3 receptor ligands

Na Ye; Qianqian Wu; Liyuan Zhu; Longtai Zheng; Bo Gao; Xuechu Zhen; Ao Zhang

doi:10.1016/j.bmc.2011.01.053

Further SAR study on 11-O-substituted aporphine analogues: Identification of highly potent dopamine D₃ receptor ligands

Na Ye, Qianqian Wu, Liyuan Zhu, Longtai Zheng, Bo Gao, Xuechu Zhen, Ao Zhang

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

18 Scopus citations

Abstract

A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D₃ receptor, low or no affinity at the D₁ and D₂ receptors. Compounds 7f and 11c stood out as the most potent at the D₃ receptor among our newly synthesized aporlogues with K_i values of 2.67 and 1.14 nM, respectively. Further assay at the 5-HT_1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with K_i values of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold more potent at the D₃ over 5-HT_1A receptors. Such D₃/5-HT_1A dual property of these compounds may be useful in the treatment of several brain disorders.

Original language	English (US)
Pages (from-to)	1999-2008
Number of pages	10
Journal	Bioorganic and Medicinal Chemistry
Volume	19
Issue number	6
DOIs	https://doi.org/10.1016/j.bmc.2011.01.053
State	Published - Mar 15 2011
Externally published	Yes

Keywords

5-HT receptor
Aporphine analogues
Arylpiperazine
Click reaction
Dopamine D receptor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2011.01.053

Cite this

@article{edd7272b3db540e091ccf53ab3547239,

title = "Further SAR study on 11-O-substituted aporphine analogues: Identification of highly potent dopamine D3 receptor ligands",

abstract = "A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D3 receptor, low or no affinity at the D1 and D2 receptors. Compounds 7f and 11c stood out as the most potent at the D3 receptor among our newly synthesized aporlogues with Ki values of 2.67 and 1.14 nM, respectively. Further assay at the 5-HT1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with Ki values of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold more potent at the D3 over 5-HT1A receptors. Such D3/5-HT1A dual property of these compounds may be useful in the treatment of several brain disorders.",

keywords = "5-HT receptor, Aporphine analogues, Arylpiperazine, Click reaction, Dopamine D receptor",

author = "Na Ye and Qianqian Wu and Liyuan Zhu and Longtai Zheng and Bo Gao and Xuechu Zhen and Ao Zhang",

note = "Funding Information: This work was supported by grants from Chinese National Science Foundation ( 81072528 , 30772625 , 30825042 ), National Science & Technology Major Project on {\textquoteleft}Key New Drug Creation and Manufacturing Program{\textquoteright}, ( 2009ZX09301-001 , 2009ZX09103-062 , 2009ZX09102-023 ), and Shanghai Commission of Science and Technology ( 10410702600 , 10JC1417100 , 10dz1910104 ). ",

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T1 - Further SAR study on 11-O-substituted aporphine analogues

T2 - Identification of highly potent dopamine D3 receptor ligands

AU - Ye, Na

AU - Wu, Qianqian

AU - Zhu, Liyuan

AU - Zheng, Longtai

AU - Gao, Bo

AU - Zhen, Xuechu

AU - Zhang, Ao

N1 - Funding Information: This work was supported by grants from Chinese National Science Foundation ( 81072528 , 30772625 , 30825042 ), National Science & Technology Major Project on ‘Key New Drug Creation and Manufacturing Program’, ( 2009ZX09301-001 , 2009ZX09103-062 , 2009ZX09102-023 ), and Shanghai Commission of Science and Technology ( 10410702600 , 10JC1417100 , 10dz1910104 ).

PY - 2011/3/15

Y1 - 2011/3/15

N2 - A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D3 receptor, low or no affinity at the D1 and D2 receptors. Compounds 7f and 11c stood out as the most potent at the D3 receptor among our newly synthesized aporlogues with Ki values of 2.67 and 1.14 nM, respectively. Further assay at the 5-HT1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with Ki values of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold more potent at the D3 over 5-HT1A receptors. Such D3/5-HT1A dual property of these compounds may be useful in the treatment of several brain disorders.

AB - A series of new aporphine analogues (aporlogues) were prepared from appropriate aporphine precursors and arylpiperazines using the Click reaction protocol. These compounds displayed good to high affinity at the D3 receptor, low or no affinity at the D1 and D2 receptors. Compounds 7f and 11c stood out as the most potent at the D3 receptor among our newly synthesized aporlogues with Ki values of 2.67 and 1.14 nM, respectively. Further assay at the 5-HT1A receptor revealed that aporlogues 7f and 11c also showed high affinity at this receptor with Ki values of 9.68 and 7.59 nM, respectively. They were 3.6- and 6.6-fold more potent at the D3 over 5-HT1A receptors. Such D3/5-HT1A dual property of these compounds may be useful in the treatment of several brain disorders.

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KW - Click reaction

KW - Dopamine D receptor

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