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Research ArticleNeuropharmacology

Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease

Nicola L. Brice, Hans H. Schiffer, Holger Monenschein, Victoria J. Mulligan, Keith Page, Justin Powell, Xiao Xu, Toni Cheung, J. Russell Burley, Huikai Sun, Louise Dickson, Sean T. Murphy, Nidhi Kaushal, Steve Sheardown, Jason Lawrence, Yun Chen, Darian Bartkowski, Anne Kanta, Joseph Russo, Natalie Hosea, Lee A. Dawson, Stephen H. Hitchcock and Mark B. Carlton
Journal of Pharmacology and Experimental Therapeutics June 2021, 377 (3) 407-416; DOI: https://doi.org/10.1124/jpet.120.000438
Nicola L. Brice
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Hans H. Schiffer
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Holger Monenschein
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Victoria J. Mulligan
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Keith Page
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Justin Powell
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Xiao Xu
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Toni Cheung
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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J. Russell Burley
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Huikai Sun
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Louise Dickson
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Sean T. Murphy
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Nidhi Kaushal
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Steve Sheardown
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Jason Lawrence
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Yun Chen
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Darian Bartkowski
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Anne Kanta
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Joseph Russo
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Natalie Hosea
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Lee A. Dawson
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Stephen H. Hitchcock
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Mark B. Carlton
Cerevance Ltd, Cambridge, United Kingdom (N.L.B., V.J.M., K.P., J.P., X.X., T.C., J.R.B., L.D., S.S., J.L., L.A.D., M.B.C.); and Takeda California, San Diego, California (H.H.S., H.M., H.S., S.T.M., N.K., Y.C., D.B., A.K., J.R., N.H., S.H.H.)
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Abstract

GPR6 is an orphan G-protein–coupled receptor that has enriched expression in the striatopallidal, indirect pathway and medium spiny neurons of the striatum. This pathway is greatly impacted by the loss of the nigro-striatal dopaminergic neurons in Parkinson disease, and modulating this neurocircuitry can be therapeutically beneficial. In this study, we describe the in vitro and in vivo pharmacological characterization of (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (CVN424), a highly potent and selective small-molecule inverse agonist for GPR6 that is currently undergoing clinical evaluation. CVN424 is brain-penetrant and shows dose-dependent receptor occupancy that attained brain 50% of receptor occupancy at plasma concentrations of 6.0 and 7.4 ng/ml in mice and rats, respectively. Oral administration of CVN424 dose-dependently increases locomotor activity and reverses haloperidol-induced catalepsy. Furthermore, CVN424 restored mobility in bilateral 6-hydroxydopamine lesion model of Parkinson disease. The presence and localization of GPR6 in medium spiny neurons of striatum postmortem samples from both nondemented control and patients with Parkinson disease were confirmed at the level of both RNA (using Nuclear Enriched Transcript Sort sequencing) and protein. This body of work demonstrates that CVN424 is a potent, orally active, and brain-penetrant GPR6 inverse agonist that is effective in preclinical models and is a potential therapeutic for improving motor function in patients with Parkinson disease.

SIGNIFICANCE STATEMENT CVN424 represents a nondopaminergic novel drug for potential use in patients with Parkinson disease.

Footnotes

    • Received November 26, 2020.
    • Accepted March 29, 2021.
  • Financial support for this work was provided by Cerevance Ltd. and Takeda Pharmaceuticals. All authors are employees of Cerevance Ltd. or Takeda Pharmaceuticals.

  • https://doi.org/10.1124/jpet.120.000438.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 377 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 3
1 Jun 2021
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Research ArticleNeuropharmacology

CVN424, a Novel GPR6 Inverse Agonist for Parkinson Disease

Nicola L. Brice, Hans H. Schiffer, Holger Monenschein, Victoria J. Mulligan, Keith Page, Justin Powell, Xiao Xu, Toni Cheung, J. Russell Burley, Huikai Sun, Louise Dickson, Sean T. Murphy, Nidhi Kaushal, Steve Sheardown, Jason Lawrence, Yun Chen, Darian Bartkowski, Anne Kanta, Joseph Russo, Natalie Hosea, Lee A. Dawson, Stephen H. Hitchcock and Mark B. Carlton
Journal of Pharmacology and Experimental Therapeutics June 1, 2021, 377 (3) 407-416; DOI: https://doi.org/10.1124/jpet.120.000438

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Research ArticleNeuropharmacology

CVN424, a Novel GPR6 Inverse Agonist for Parkinson Disease

Nicola L. Brice, Hans H. Schiffer, Holger Monenschein, Victoria J. Mulligan, Keith Page, Justin Powell, Xiao Xu, Toni Cheung, J. Russell Burley, Huikai Sun, Louise Dickson, Sean T. Murphy, Nidhi Kaushal, Steve Sheardown, Jason Lawrence, Yun Chen, Darian Bartkowski, Anne Kanta, Joseph Russo, Natalie Hosea, Lee A. Dawson, Stephen H. Hitchcock and Mark B. Carlton
Journal of Pharmacology and Experimental Therapeutics June 1, 2021, 377 (3) 407-416; DOI: https://doi.org/10.1124/jpet.120.000438
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