使用阿立哌唑作为先导化合物，合成并表征选择性多巴胺 D₂ 受体配体。
Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound.
机构信息
Division of Radiological Sciences, Washington University School of Medicine, Mallinckrodt Institute of Radiology, 510 S. Kingshighway, St. Louis, MO 63110, USA.
出版信息
Bioorg Med Chem. 2011 Jun 1;19(11):3502-11. doi: 10.1016/j.bmc.2011.04.021. Epub 2011 Apr 16.
Abstract
A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(₂-like) dopamine receptors. These compounds also share structural elements with the classical D(₂-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D₂ receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D₂ versus D₃ receptor binding selectivity and (c) be partial agonists at both the D₂ and D₃ receptor subtype.
摘要
一系列与阿立哌唑（1）结构相关的化合物，阿立哌唑是一种临床用于治疗精神分裂症、双相情感障碍和抑郁症的非典型抗精神病药和抗抑郁药，已被制备并评估了它们对 D₂样多巴胺受体的亲和力。这些化合物还与经典的 D₂样多巴胺受体拮抗剂氟哌啶醇、N-甲基哌嗪酮、多潘立酮和苯海索具有结构元素。两种新化合物，7-(4-(4-(2-甲氧基苯基)哌嗪-1-基)丁氧基)-3,4-二氢喹啉-2(1H)-酮草酸盐（6）和 7-(4-(4-(2-(2-乙氧基)苯基)哌嗪-1-基)丁氧基)-3,4-二氢喹啉-2(1H)-酮草酸盐（7），（a）与 D₂受体亚型具有高亲和力（K(i)值<0.3 nM），（b）表现出对 D₃受体的>50 倍结合选择性，（c）在 D₂和 D₃受体亚型上均为部分激动剂。
相似文献
1
Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound.
Bioorg Med Chem. 2011 Jun 1;19(11):3502-11. doi: 10.1016/j.bmc.2011.04.021. Epub 2011 Apr 16.
2
Comparison of the binding and functional properties of two structurally different D2 dopamine receptor subtype selective compounds.
ACS Chem Neurosci. 2012 Dec 19;3(12):1050-62. doi: 10.1021/cn300142q. Epub 2012 Oct 12.
3
Synthesis and characterization of selective dopamine D2 receptor antagonists.
Bioorg Med Chem. 2006 Feb 1;14(3):815-25. doi: 10.1016/j.bmc.2005.09.008. Epub 2005 Nov 8.
4
Evaluation of N-phenyl homopiperazine analogs as potential dopamine D3 receptor selective ligands.
Bioorg Med Chem. 2013 Jun 1;21(11):2988-98. doi: 10.1016/j.bmc.2013.03.074. Epub 2013 Apr 6.
5
Antidepressant and antipsychotic activity of new quinoline- and isoquinoline-sulfonamide analogs of aripiprazole targeting serotonin 5-HT₁A/5-HT₂A/5-HT₇ and dopamine D₂/D₃ receptors.
Eur J Med Chem. 2013 Feb;60:42-50. doi: 10.1016/j.ejmech.2012.11.042. Epub 2012 Dec 5.
6
Synthesis and characterization of selective dopamine D2 receptor antagonists. 2. Azaindole, benzofuran, and benzothiophene analogs of L-741,626.
Bioorg Med Chem. 2010 Jul 15;18(14):5291-300. doi: 10.1016/j.bmc.2010.05.052. Epub 2010 May 24.
7
Synthesis and pharmacological evaluation of potent and highly selective D3 receptor ligands: inhibition of cocaine-seeking behavior and the role of dopamine D3/D2 receptors.
J Med Chem. 2003 Aug 28;46(18):3822-39. doi: 10.1021/jm0211220.
8
Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors.
Eur J Pharmacol. 2008 Nov 12;597(1-3):27-33. doi: 10.1016/j.ejphar.2008.09.008. Epub 2008 Sep 20.
9
Synthesis and structure-activity relationships of naphthamides as dopamine D3 receptor ligands.
J Med Chem. 2001 May 24;44(11):1815-26. doi: 10.1021/jm0100077.
10
Synthesis and pharmacological evaluation of fluorine-containing D₃ dopamine receptor ligands.
J Med Chem. 2011 Mar 24;54(6):1555-64. doi: 10.1021/jm101323b. Epub 2011 Feb 24.
引用本文的文献
1
Synthesis of bitopic ligands based on fallypride and evaluation of their affinity and selectivity towards dopamine D and D receptors.
Eur J Med Chem. 2023 Dec 5;261:115751. doi: 10.1016/j.ejmech.2023.115751. Epub 2023 Sep 9.
2
Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models.
Psychopharmacology (Berl). 2023 Apr;240(4):1011-1031. doi: 10.1007/s00213-023-06347-1. Epub 2023 Feb 28.
3
Identification and Characterization of ML321: A Novel and Highly Selective D Dopamine Receptor Antagonist with Efficacy in Animal Models That Predict Atypical Antipsychotic Activity.
ACS Pharmacol Transl Sci. 2022 Dec 30;6(1):151-170. doi: 10.1021/acsptsci.2c00202. eCollection 2023 Jan 13.
4
Design and Synthesis of Conformationally Flexible Scaffold as Bitopic Ligands for Potent D-Selective Antagonists.
Int J Mol Sci. 2022 Dec 27;24(1):432. doi: 10.3390/ijms24010432.
5
Structure Activity Relationships for a Series of Eticlopride-Based Dopamine D/D Receptor Bitopic Ligands.
J Med Chem. 2021 Oct 28;64(20):15313-15333. doi: 10.1021/acs.jmedchem.1c01353. Epub 2021 Oct 12.
6
Synthesis and In Vitro Evaluation of Novel Dopamine Receptor D 3,4-dihydroquinolin-2(1)-one Derivatives Related to Aripiprazole.
Biomolecules. 2021 Aug 24;11(9):1262. doi: 10.3390/biom11091262.
7
BiasNet: A Model to Predict Ligand Bias Toward GPCR Signaling.
J Chem Inf Model. 2021 Sep 27;61(9):4190-4199. doi: 10.1021/acs.jcim.1c00317. Epub 2021 Aug 16.
8
C- and F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future.
Biomedicines. 2021 Jan 22;9(2):108. doi: 10.3390/biomedicines9020108.
9
Ligand with Two Modes of Interaction with the Dopamine D Receptor-An Induced-Fit Mechanism of Insurmountable Antagonism.
ACS Chem Neurosci. 2020 Oct 7;11(19):3130-3143. doi: 10.1021/acschemneuro.0c00477. Epub 2020 Sep 15.
10
Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D Receptor (DR) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).
J Med Chem. 2019 May 23;62(10):5132-5147. doi: 10.1021/acs.jmedchem.9b00412. Epub 2019 May 6.
本文引用的文献
1
Effect of cyclosporin A on the uptake of D3-selective PET radiotracers in rat brain.
Nucl Med Biol. 2011 Jul;38(5):725-39. doi: 10.1016/j.nucmedbio.2011.01.002. Epub 2011 Mar 3.
2
Endogenous dopamine (DA) competes with the binding of a radiolabeled D₃ receptor partial agonist in vivo: a positron emission tomography study.
Synapse. 2011 Aug;65(8):724-32. doi: 10.1002/syn.20891. Epub 2011 Mar 21.
3
Synthesis and characterization of selective dopamine D2 receptor antagonists. 2. Azaindole, benzofuran, and benzothiophene analogs of L-741,626.
Bioorg Med Chem. 2010 Jul 15;18(14):5291-300. doi: 10.1016/j.bmc.2010.05.052. Epub 2010 May 24.
4
Positron emission tomography imaging of dopamine D₂/₃ receptors in the human cortex with [¹¹C]FLB 457: reproducibility studies.
Synapse. 2011 Jan;65(1):35-40. doi: 10.1002/syn.20813.
5
6
Further evaluation of the carbon11-labeled D(2/3) agonist PET radiotracer PHNO: reproducibility in tracer characteristics and characterization of extrastriatal binding.
Synapse. 2010 Apr;64(4):301-12. doi: 10.1002/syn.20718.
7
Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways.
Synapse. 2010 Mar;64(3):251-66. doi: 10.1002/syn.20725.
8
[(3)H]4-(Dimethylamino)-N-[4-(4-(2-methoxyphenyl)piperazin- 1-yl)butyl]benzamide, a selective radioligand for dopamine D(3) receptors. I. In vitro characterization.
Synapse. 2009 Sep;63(9):717-28. doi: 10.1002/syn.20652.
9
Positron emission tomography imaging of amphetamine-induced dopamine release in the human cortex: a comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride.
Synapse. 2009 Jun;63(6):447-61. doi: 10.1002/syn.20628.
10
4-[omega-[4-arylpiperazin-1-yl]alkoxy]phenyl)imidazo[1,2-a]pyridine derivatives: fluorescent high-affinity dopamine D3 receptor ligands as potential probes for receptor visualization.
J Med Chem. 2007 Oct 4;50(20):5043-7. doi: 10.1021/jm070721+. Epub 2007 Sep 12.
Zotero 插件