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Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists
Journal article   Open access   Peer reviewed

Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists

Wei Xu, Xiaozhao Wang, Aaron M Tocker, Peng Huang, Maarten E A Reith, Lee-Yuan Liu-Chen, Amos B Smith, 3rd and Sandhya Kortagere
ACS chemical neuroscience, v 8(3), pp 486-500
15 Mar 2017
DOI: https://doi.org/10.1021/acschemneuro.6b00221
PMID: 27801563
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5813806View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Animals Benzazepines - pharmacokinetics Butylamines - chemistry Butylamines - pharmacology CHO Cells Cricetulus Dopamine Antagonists - pharmacokinetics Dopamine Antagonists - pharmacology Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics HEK293 Cells Humans Models, Molecular Molecular Docking Simulation Phosphorylation - drug effects Phosphorylation - genetics Protein Binding - drug effects Receptors, Dopamine D2 - genetics Receptors, Dopamine D2 - metabolism Receptors, Dopamine D3 - agonists Receptors, Dopamine D3 - genetics Receptors, Dopamine D3 - metabolism Signal Transduction - drug effects Signal Transduction - genetics Sulfur Isotopes - pharmacokinetics Transfection Tritium - pharmacokinetics
Dopamine receptors play an integral role in controlling brain physiology. Importantly, subtype selective agonists and antagonists of dopamine receptors with biased signaling properties have been successful in treating psychiatric disorders with a low incidence of side effects. To this end, we recently designed and developed SK609, a dopamine D3 receptor (D3R) selective agonist that has atypical signaling properties. SK609 has shown efficacy in reversing akinesia and reducing L-dopa-induced dyskinesia in a hemiparkinsonian rats. In the current study, we demonstrate that SK609 has high selectivity for D3R with no binding affinity on D2R high- or low-affinity state when tested at a concentration of 10 μM. In addition, SK609 and its analogues do not induce desensitization of D3R as determined by repeated agonist treatment response in phosphorylation of ERK1/2 functional assay. Most significantly, SK609 and its analogues preferentially signal through the G-protein-dependent pathway and do not recruit β-arrestin-2, suggesting a functional bias toward the G-protein-dependent pathway. Structure-activity relationship (SAR) studies using analogues of SK609 demonstrate that the molecules bind at the orthosteric site by maintaining the conserved salt bridge interactions with aspartate 110 on transmembrane 3 and aryl interactions with histidine 349 on transmembrane 6, in addition to several hydrophobic interactions with residues from transmembranes 5 and 6. The compounds follow a strict SAR with reference to the three pharmacophore elements: substituted phenyl ring, length of the linker connecting phenyl ring and amine group, and orientation and hydrophobic branching groups at the amine among SK609 analogues for efficacy and functional selectivity. These features of SK609 and the analogues suggest that biased signaling is an inherent property of this series of molecules.

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Collaboration types
Domestic collaboration
Web of Science research areas
Biochemistry & Molecular Biology
Chemistry, Medicinal
Neurosciences
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