title: Functional Characterization of a Novel Series of Biased Signaling Dopamine D3 Receptor Agonists.
abstract: 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.
authors: Wei
authors: W
authors: Xu
authors: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19102, United States.
authors: Xiaozhao
authors: X
authors: Wang
authors: Aaron M
authors: AM
authors: Tocker
authors: Department of Pharmacology, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
authors: Peng
authors: P
authors: Huang
authors: Department of Psychiatry, Biochemistry and Molecular Pharmacology, NYU School of Medicine , New York, New York 10016, United States.
authors: Maarten E A
authors: ME
authors: Reith
authors: Department of Pharmacology, Temple University School of Medicine , Philadelphia, Pennsylvania 19140, United States.
authors: Lee-Yuan
authors: LY
authors: Liu-Chen
authors: Department of Chemistry, University of Pennsylvania , Philadelphia, Pennsylvania 19102, United States.
authors: Amos B
authors: AB
authors: Smith
authors: Sandhya
authors: S
authors: Kortagere
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics; D002082:Butylamines / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D003412:Cricetulus; D018492:Dopamine Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D014162:Transfection; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C000593232:4-(2-chlorophenyl)butan-2-amine; D001552:Benzazepines; D002082:Butylamines; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C534628:SCH 23390; D013460:Sulfur Isotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Biased signaling; G-protein-dependent signaling; desensitization; dopamine D3 receptors; functional selectivity; hybrid structure-based design; structure−function relationship; β-arrestin