RT Journal Article
SR Electronic
T1 Development of CVN424: a selective and novel GPR6 inverse agonist effective in models of Parkinson's Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000438
DO 10.1124/jpet.120.000438
A1 Brice, Nicola L
A1 Schiffer, Hans H
A1 Monenschein, Holger
A1 Mulligan, Victoria J
A1 Page, Keith
A1 Powell, Justin
A1 Xu, Xiao
A1 Cheung, Toni
A1 Burley, J Russell
A1 Sun, Huikai
A1 Dickson, Louise
A1 Murphy, Sean T
A1 Kaushal, Nidhi
A1 Sheardown, Steven
A1 Lawrence, Jason
A1 Chen, Yun
A1 Bartkowski, Darian
A1 Kanta, Anne
A1 Russo, Joseph
A1 Hosea, Natalie
A1 Dawson, Lee A
A1 Hitchcock, Stephen H
A1 Carlton, Mark B
YR 2021
UL http://jpet.aspetjournals.org/content/early/2021/04/01/jpet.120.000438.abstract
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.