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

Bioorg Med Chem. 2011 Mar 15;19(6):1999-2008. doi: 10.1016/j.bmc.2011.01.053. Epub 2011 Jan 31.

Authors

Na Ye¹, QianQian Wu, Liyuan Zhu, Longtai Zheng, Bo Gao, Xuechu Zhen, Ao Zhang

Affiliation

¹ Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

PMID: 21334902
DOI: 10.1016/j.bmc.2011.01.053

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 D(3) receptor, low or no affinity at the D(1) and D(2) receptors. Compounds 7f and 11c stood out as the most potent at the D(3) 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 D(3) over 5-HT(1A) receptors. Such D(3)/5-HT(1A) dual property of these compounds may be useful in the treatment of several brain disorders.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aporphines / chemical synthesis
Aporphines / chemistry*
Aporphines / pharmacology
Dopamine Agents / chemical synthesis
Dopamine Agents / chemistry*
Dopamine Agents / pharmacology
Dopamine D2 Receptor Antagonists
HEK293 Cells
Humans
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology
Protein Binding
Receptor, Serotonin, 5-HT1A / chemistry
Receptor, Serotonin, 5-HT1A / metabolism
Receptors, Dopamine D1 / antagonists & inhibitors
Receptors, Dopamine D1 / metabolism
Receptors, Dopamine D2 / metabolism
Receptors, Dopamine D3 / agonists
Receptors, Dopamine D3 / antagonists & inhibitors
Receptors, Dopamine D3 / metabolism*
Stereoisomerism
Structure-Activity Relationship

Substances

11-((1-(3-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-1,2,3-triazol-4-yl)methoxy)-N-propylnoraporphine
11-(3-(4-((4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-1H-1,2,3-triazol-1-yl)propoxy)-N-propylnoraporphine
Aporphines
Dopamine Agents
Dopamine D2 Receptor Antagonists
Piperazines
Receptors, Dopamine D1
Receptors, Dopamine D2
Receptors, Dopamine D3
Receptor, Serotonin, 5-HT1A
aporphine