TY - JOUR
T1 - Discovery, Optimization, and Characterization of ML417
T2 - A Novel and Highly Selective D3 Dopamine Receptor Agonist
AU - Moritz, Amy E.
AU - Free, R. Benjamin
AU - Weiner, Warren S.
AU - Akano, Emmanuel O.
AU - Gandhi, Disha
AU - Abramyan, Ara
AU - Keck, Thomas M.
AU - Ferrer, Marc
AU - Hu, Xin
AU - Southall, Noel
AU - Steiner, Joseph
AU - Aubé, Jeffrey
AU - Shi, Lei
AU - Frankowski, Kevin J.
AU - Sibley, David R.
N1 - Funding Information:
The authors thank Benjamin Neuenswander for preparative and analytical HPLC and Patrick Porubsky for compound management. The authors thank the University of North Carolina’s Department of Chemistry Mass Spectrometry Core Laboratory for their assistance with mass spectrometry analysis. Q Exactive HF-X system HRMS determinations were supported by the National Science Foundation under Grant No. (CHE-1726291). The authors thank Shaomeng Wang, Ph.D. at the University of Michigan, for the kind gift of Compound CJ-1639. Receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, contract # HHSN-271-2018-00023-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth MD, Ph.D. at the University of North Carolina at Chapel Hill, and Project Officer Jamie Driscoll at NIMH, Bethesda, MD. Support for this research was provided by the National Institute of Neurological Disorders and Stroke-Intramural Research Program, the National Institute on Drug Abuse-Intramural Research Program (Z1A DA000609), and Molecular Libraries Initiative funding to the University of Kansas Specialized Chemistry Center (U54HG005031), and generous support was provided by the Eshelman Institute for Innovation at the UNC Eshelman School of Pharmacy.
Publisher Copyright:
Copyright © 2020 American Chemical Society.
PY - 2020/5/28
Y1 - 2020/5/28
N2 - To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
AB - To identify novel D3 dopamine receptor (D3R) agonists, we conducted a high-throughput screen using a β-arrestin recruitment assay. Counterscreening of the hit compounds provided an assessment of their selectivity, efficacy, and potency. The most promising scaffold was optimized through medicinal chemistry resulting in enhanced potency and selectivity. The optimized compound, ML417 (20), potently promotes D3R-mediated β-arrestin translocation, G protein activation, and ERK1/2 phosphorylation (pERK) while lacking activity at other dopamine receptors. Screening of ML417 against multiple G protein-coupled receptors revealed exceptional global selectivity. Molecular modeling suggests that ML417 interacts with the D3R in a unique manner, possibly explaining its remarkable selectivity. ML417 was also found to protect against neurodegeneration of dopaminergic neurons derived from iPSCs. Together with promising pharmacokinetics and toxicology profiles, these results suggest that ML417 is a novel and uniquely selective D3R agonist that may serve as both a research tool and a therapeutic lead for the treatment of neuropsychiatric disorders.
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U2 - 10.1021/acs.jmedchem.0c00424
DO - 10.1021/acs.jmedchem.0c00424
M3 - Article
C2 - 32342685
AN - SCOPUS:85085585987
SN - 0022-2623
VL - 63
SP - 5526
EP - 5567
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 10
ER -