Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

American Chemical Society full text link American Chemical Society Free PMC article
Full text links

Actions

Share

.2017 Jan 26;60(2):580-593.
doi: 10.1021/acs.jmedchem.6b01148. Epub 2017 Jan 5.

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor

Affiliations

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D3 Receptor

Mayako Michino et al. J Med Chem..

Abstract

Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (R)-enantiomers are antagonists/weak partial agonists, whereas the (S)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D3R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (S)-enantiomers, but not by the (R)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Functional efficacies measured by the Go BRET activation assay
The (R)-enantiomers ((R)-9, -4, -6) and the analogues without the linker 3-OH group (10, 3, 11) are antagonists, whereas the (S)-enantiomers ((S)-9, -4, -6) are partial agonists. Emax is the % of dopamine efficacy. The efficacies of (S)-enantiomers are significantly different from their corresponding (R)-enantiomers and analogues without a linker (in each case, P < 0.005 using one-way ANOVA followed by post hoc Tukey test).
Figure 2
Figure 2. Functional efficacies measured by the β-arrestin recruitment assay
The (R)-enantiomers ((R)-9, -4, -6) are antagonists, whereas the (S)-enantiomers ((S)-9, -4, -6) are partial agonists. Emax is the % of dopamine efficacy. NA, no activity. The efficacies of (S)-enantiomers are significantly different from their corresponding (R)-enantiomers; (S)-9 efficacy is significant different from (S)-4 or (S)-6 efficacy (in each case, P < 0.0001 using one-way ANOVA followed by post hoc Tukey test).
Figure 3
Figure 3. Differential binding modes of (R)- vs (S)-enantiomers
(a) The overall binding mode of the full-length 2,3-diCl phenylpiperazine compound. (b) The dihedral angle in the linker region. Panels (c–e) show the representative binding modes of (R)-, (S)-9, and10 (C), (R)-, (S)-4 and3 (d), and (R)- and (S)-6 (e). The distribution of linker dihedral angle (C1-C2-C3-C4) differs substantially between the (R)- and (S)-enantiomers for the full-length compounds (f,g), whereas they are comparable for the synthons (h). Ligands are shown as sticks. TMs 6 and 7 are not shown for clarity.
Figure 4
Figure 4. Comparative receptor conformational analysis using PIA-GPCR
Heatmaps show the differences in the distances among TM sub-segments (left panels), and the distances among Cα atoms of ligand binding site residues (right panels), comparing between (R)- and (S)-9-bound frames (a); (R)- and (S)-4-bound frames (b); (R)- and (S)-6-bound frames (c). The color is scaled from blue to red, corresponding to the increase and decrease, respectively, of the metric values in the (S)-enantiomers bound state compared to the (R)-enantiomers bound state.
Figure 5
Figure 5. Common rearrangements at the TM5-TM6 interface
Scatterplots of X1-dihedral angle of Phe3466.52 and the distance between TMs 5 and 6 compared between (R)- and (S)-9, 4, 6. The common trend of the differences between the (R)- and (S)-enantiomer bound conditions suggest that the rotamer change of Phe6.52 is correlated with the observed movements of TMs 5 and 6 during partial activation.
Figure 6
Figure 6. Molecular mechanism of D3R partial activation
Schematic representation shows the common trend of movements of TM helices and the extracellular loop regions based on the comparisons between the antagonist- and partial agonist-bound D3R MD simulations.
Scheme 1
Scheme 1. Synthesis of full-length D3R ligandsa
aReagents and conditions: (a) (i) quinoline-3-carboxylic acid, CDI, THF, room temperature, 2 h; (ii) appropriate 4-arylpiperazine amine, THF, 0 °C to room temperature, overnight.
Scheme 2
Scheme 2. Synthesis of (R)- and (S)-synthonsa
aReagents and conditions: (a) appropriate epoxide, isopropanol, reflux, overnight.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Heidbreder CA, Newman AH. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann. N. Y. Acad. Sci. 2010;1187:4–34. - PMC - PubMed
    1. Stemp G, Ashmeade T, Branch CL, Hadley MS, Hunter AJ, Johnson CN, Nash DJ, Thewlis KM, Vong AK, Austin NE, Jeffrey P, Avenell KY, Boyfield I, Hagan JJ, Middlemiss DN, Reavill C, Riley GJ, Routledge C, Wood M. Design and synthesis of trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarboxamide (SB-277011): A potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and CNS penetration in the rat. J. Med. Chem. 2000;43:1878–1885. - PubMed
    1. Reavill C, Taylor SG, Wood MD, Ashmeade T, Austin NE, Avenell KY, Boyfield I, Branch CL, Cilia J, Coldwell MC, Hadley MS, Hunter AJ, Jeffrey P, Jewitt F, Johnson CN, Jones DN, Medhurst AD, Middlemiss DN, Nash DJ, Riley GJ, Routledge C, Stemp G, Thewlis KM, Trail B, Vong AK, Hagan JJ. Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A. J. Pharmacol. Exp. Ther. 2000;294:1154–1165. - PubMed
    1. Vorel SR, Ashby CR, Jr, Paul M, Liu X, Hayes R, Hagan JJ, Middlemiss DN, Stemp G, Gardner EL. Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J. Neurosci. 2002;22:9595–9603. - PMC - PubMed
    1. Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature. 1999;400:371–375. - PubMed

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full text links
American Chemical Society full text link American Chemical Society Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp