PT  - JOURNAL ARTICLE
AU  - Nicola L Brice
AU  - Hans H Schiffer
AU  - Holger Monenschein
AU  - Victoria J Mulligan
AU  - Keith Page
AU  - Justin Powell
AU  - Xiao Xu
AU  - Toni Cheung
AU  - J Russell Burley
AU  - Huikai Sun
AU  - Louise Dickson
AU  - Sean T Murphy
AU  - Nidhi Kaushal
AU  - Steven Sheardown
AU  - Jason Lawrence
AU  - Yun Chen
AU  - Darian Bartkowski
AU  - Anne Kanta
AU  - Joseph Russo
AU  - Natalie Hosea
AU  - Lee A Dawson
AU  - Stephen H Hitchcock
AU  - Mark B Carlton
TI  - Development of CVN424: a selective and novel GPR6 inverse agonist effective in models of Parkinson's Disease
AID  - 10.1124/jpet.120.000438
DP  - 2021 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - JPET-AR-2020-000438
4099  - http://jpet.aspetjournals.org/content/early/2021/04/01/jpet.120.000438.short
4100  - http://jpet.aspetjournals.org/content/early/2021/04/01/jpet.120.000438.full
AB  - GPR6 is an orphan GPCR that has enriched expression in the striatopallidal, indirect pathway, medium spiny neurons of the striatum. This pathway is greatly impacted by the loss of the nigro-striatal dopaminergic neurons in Parkinson's disease and modulating this neurocircuitry can be therapeutically beneficial. In this study we describe the in vitro and in vivo pharmacological characterization of CVN424, a highly potent and selective small molecule inverse agonist for GPR6 which is currently undergoing clinical evaluation. CVN424 is brain penetrant and shows dose dependent receptor occupancy that attained brain RO50 at plasma concentrations of 6.0 ng/ml 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-OHDA lesion model of Parkinson's disease. The presence and localization of GPR6 in medium spiny neurons of striatum postmortem samples from both non-demented control and Parkinson's disease patients was confirmed at the level of both RNA (using NETSseq) and protein. This body of work demonstrates that CVN424 is a potent, orally active and brain penetrant GPR6 inverse agonist which is effective in pre-clinical models and is a potential therapeutic for improving motor function in patients with Parkinson's disease. Significance Statement CVN424 represents a non-dopaminergic novel drug for potential use in patients with Parkinson’s disease.