Home LiteratureArticle Details
PMID: 22845053 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Structure-functional selectivity relationship studies of β-arrestin-biased dopamine D₂ receptor agonists.

Journal of medicinal chemistry ·Vol. 55 ·No. 16 ·2012-08-23 ·Pages 7141-53

Chen X, Sassano MF, Zheng L, Setola V, Chen M, Bai X, Frye SV, Wetsel WC, Roth BL, Jin J

Abstract

Functionally selective G protein-coupled receptor (GPCR) ligands, which differentially modulate canonical and noncanonical signaling, are extremely useful for elucidating key signal transduction pathways essential for both the therapeutic actions and side effects of drugs. However, few such ligands have been created, and very little purposeful attention has been devoted to studying what we term: "structure-functional selectivity relationships" (SFSR). We recently disclosed the first β-arrestin-biased dopamine D(2) receptor (D(2)R) agonists UNC9975 (44) and UNC9994 (36), which have robust in vivo antipsychotic drug-like activities. Here we report the first comprehensive SFSR studies focused on exploring four regions of the aripiprazole scaffold, which resulted in the discovery of these β-arrestin-biased D(2)R agonists. These studies provide a successful proof-of-concept for how functionally selective ligands can be discovered.

MeSH Terms
Animals Antipsychotic Agents/chemical synthesis,chemistry,pharmacology Aripiprazole Arrestins/genetics,metabolism CHO Cells Cricetinae Cricetulus Cyclic AMP/biosynthesis Female HEK293 Cells Humans Hyperkinesis/chemically induced,drug therapy Ligands Male Mice Mice, Knockout Phencyclidine Piperazines/chemical synthesis,chemistry,pharmacology Quinolones/chemical synthesis,chemistry,pharmacology Radioligand Assay Receptors, Dopamine D2/agonists,metabolism Structure-Activity Relationship beta-Arrestins
Chemicals
Antipsychotic Agents Arrestins Ligands Piperazines Quinolones Receptors, Dopamine D2 beta-Arrestins Aripiprazole Cyclic AMP Phencyclidine
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chen Xin
Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
Sassano Maria F
Zheng Lianyou
Setola Vincent
Chen Meng
Bai Xu
Frye Stephen V
Wetsel William C
Roth Bryan L
Jin Jian
References (45)
45 references, click to expand
  1. Inverse agonist activity of beta-adrenergic antagonists.
    Mol Pharmacol. 1994 Mar;45(3):490-9 PMID: 7908406
  2. 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 PMID: 21536445
  3. Aripiprazole has functionally selective actions at dopamine D2 receptor-mediated signaling pathways.
    Neuropsychopharmacology. 2007 Jan;32(1):67-77 PMID: 16554739
  4. 9-Dihydroxy-2,3,7,11b-tetrahydro-1H-naph[1,2,3-de]isoquinoline: a potent full dopamine D1 agonist containing a rigid-beta-phenyldopamine pharmacophore.
    J Med Chem. 1996 Jan 19;39(2):549-55 PMID: 8558526
  5. Functional selectivity of dopamine receptor agonists. I. Selective activation of postsynaptic dopamine D2 receptors linked to adenylate cyclase.
    J Pharmacol Exp Ther. 2002 Jun;301(3):1166-78 PMID: 12023552
  6. [Design, synthesis and vasorelaxant activity of R, S-1-(substituted phenyl)-4-[3-(naphtha-1-yl-oxy)-2-hydroxypropyl]-piperazine derivatives].
    Yao Xue Xue Bao. 2007 Jul;42(7):735-40 PMID: 17882957
  7. Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.
    J Med Chem. 2009 Jan 8;52(1):151-69 PMID: 19072656
  8. NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities.
    J Org Chem. 1997 Oct 17;62(21):7512-7515 PMID: 11671879
  9. Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?
    Curr Pharm Des. 2010;16(5):488-501 PMID: 19909227
  10. Beta-arrestin-dependent formation of beta2 adrenergic receptor-Src protein kinase complexes.
    Science. 1999 Jan 29;283(5402):655-61 PMID: 9924018
  11. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers.
    J Clin Pharmacol. 2004 Feb;44(2):179-87 PMID: 14747427
  12. 2-Phenylpyrroles as conformationally restricted benzamide analogues. A new class of potential antipsychotics. 1.
    J Med Chem. 1987 Nov;30(11):2099-104 PMID: 2889830
  13. Constitutively active 5-hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands.
    J Biol Chem. 1994 Apr 22;269(16):11687-90 PMID: 7909313
  14. N-arylpiperazinyl-N'-propylamino derivatives of heteroaryl amides as functional uroselective alpha 1-adrenoceptor antagonists.
    J Med Chem. 1997 Aug 15;40(17):2674-87 PMID: 9276013
  15. 2-Phenylpyrroles as conformationally restricted benzamide analogues. A new class of potential antipsychotics. 2.
    J Med Chem. 1988 Oct;31(10):1934-40 PMID: 2902226
  16. A beta-arrestin-biased agonist of the parathyroid hormone receptor (PTH1R) promotes bone formation independent of G protein activation.
    Sci Transl Med. 2009 Oct 7;1(1):1ra1 PMID: 20368153
  17. Discovery of β-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy.
    Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18488-93 PMID: 22025698
  18. Enhanced morphine analgesia in mice lacking beta-arrestin 2.
    Science. 1999 Dec 24;286(5449):2495-8 PMID: 10617462
  19. Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus.
    Mol Pharmacol. 1998 Jul;54(1):94-104 PMID: 9658194
  20. Novel antipsychotic agents with dopamine autoreceptor agonist properties: synthesis and pharmacology of 7-[4-(4-phenyl-1-piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives.
    J Med Chem. 1998 Feb 26;41(5):658-67 PMID: 9513593
  21. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile.
    J Pharmacol Exp Ther. 2010 Apr;333(1):328-40 PMID: 20093397
  22. Transduction of receptor signals by beta-arrestins.
    Science. 2005 Apr 22;308(5721):512-7 PMID: 15845844
  23. Beta-arrestin-biased ligands at seven-transmembrane receptors.
    Trends Pharmacol Sci. 2007 Aug;28(8):416-22 PMID: 17644195
  24. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes.
    Neuropsychopharmacology. 1999 Jun;20(6):612-27 PMID: 10327430
  25. The genetic design of signaling cascades to record receptor activation.
    Proc Natl Acad Sci U S A. 2008 Jan 8;105(1):64-9 PMID: 18165312
  26. Evidence that LY-141865 specifically stimulates the D-2 dopamine receptor.
    Nature. 1981 Jul 30;292(5822):463-5 PMID: 7254340
  27. Clozapine and other 5-hydroxytryptamine-2A receptor antagonists alter the subcellular distribution of 5-hydroxytryptamine-2A receptors in vitro and in vivo.
    Neuroscience. 1999;91(2):599-606 PMID: 10366017
  28. An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.
    Cell. 2005 Jul 29;122(2):261-73 PMID: 16051150
  29. Studies on 2(1H)-quinolinone derivatives as neuroleptic agents I. Synthesis and biological activities of (4-phenyl-1-piperazinyl)-propoxy-2(1H)-quinolinone derivatives.
    Chem Pharm Bull (Tokyo). 1988 Nov;36(11):4377-88 PMID: 2907733
  30. Functional selectivity of dopamine receptor agonists. II. Actions of dihydrexidine in D2L receptor-transfected MN9D cells and pituitary lactotrophs.
    J Pharmacol Exp Ther. 2002 Jun;301(3):1179-89 PMID: 12023553
  31. Intrinsic efficacy of antipsychotics at human D2, D3, and D4 dopamine receptors: identification of the clozapine metabolite N-desmethylclozapine as a D2/D3 partial agonist.
    J Pharmacol Exp Ther. 2005 Dec;315(3):1278-87 PMID: 16135699
  32. Serotonergic antagonist effects on trafficking of serotonin 5-HT2A receptors in vitro and in vivo.
    Ann N Y Acad Sci. 1998 Dec 15;861:121-7 PMID: 9928248
  33. GPCR functional selectivity has therapeutic impact.
    Trends Pharmacol Sci. 2007 Aug;28(8):390-6 PMID: 17629962
  34. Rapid agonist-induced internalization of the 5-hydroxytryptamine2A receptor occurs via the endosome pathway in vitro.
    Mol Pharmacol. 1996 Aug;50(2):306-13 PMID: 8700138
  35. Functional selectivity and classical concepts of quantitative pharmacology.
    J Pharmacol Exp Ther. 2007 Jan;320(1):1-13 PMID: 16803859
  36. Discovery of PF-00217830: aryl piperazine napthyridinones as D2 partial agonists for schizophrenia and bipolar disorder.
    Bioorg Med Chem Lett. 2011 May 1;21(9):2621-5 PMID: 21353774
  37. Effects of aripiprazole/OPC-14597 on motor activity, pharmacological models of psychosis, and brain activity in rats.
    Neuropharmacology. 2008 Feb;54(2):405-16 PMID: 18054053
  38. Multiple mechanisms of serotonergic signal transduction.
    Life Sci. 1987 Aug 31;41(9):1051-64 PMID: 2441225
  39. Characterization of dopaminergic compounds at hD2short, hD4.2 and hD4.7 receptors in agonist-stimulated [35S]GTPgammaS binding assays.
    Naunyn Schmiedebergs Arch Pharmacol. 2000 May;361(5):498-504 PMID: 10832603
  40. Inverse agonist actions of typical and atypical antipsychotic drugs at the human 5-hydroxytryptamine(2C) receptor.
    J Pharmacol Exp Ther. 2001 Oct;299(1):83-9 PMID: 11561066
  41. Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo.
    J Neurosci. 2007 Jan 24;27(4):881-5 PMID: 17251429
  42. Long-term antidepressant treatment decreases spiroperidol-labeled serotonin receptor binding.
    Science. 1980 Oct 3;210(4465):88-90 PMID: 6251550
  43. Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy.
    J Med Chem. 1989 May;32(5):1052-6 PMID: 2565400
  44. Differential phospholipase C activation by phenylalkylamine serotonin 5-HT 2A receptor agonists.
    J Neurochem. 2005 Dec;95(6):1575-84 PMID: 16277614
  45. Arresting serotonin.
    Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):831-2 PMID: 18195368
Article Info
Journal
Journal of medicinal chemistry
Abbr.
J Med Chem
ISSN
1520-4804
DOI
10.1021/jm300603y
Published
2012-08-23
Epub
2012-00-13
Pages
7141-53
Language
English
Region
United States
NLM ID
9716531
PMCID
PMC3443605
Subset
IM
Grants
NIMH NIH HHS · U19 MH082441 · United States
NIMH NIH HHS · U19MH082441S1 · United States
NIMH NIH HHS · U19MH082441 · United States
External Links
PubMed source DOI: 10.1021/jm300603y PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2