RT Journal Article
SR Electronic
T1 Development of CVN424: A Selective and Novel GPR6 Inverse Agonist Effective in Models of Parkinson Disease
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 407
OP 416
DO 10.1124/jpet.120.000438
VO 377
IS 3
A1 Nicola L. Brice
A1 Hans H. Schiffer
A1 Holger Monenschein
A1 Victoria J. Mulligan
A1 Keith Page
A1 Justin Powell
A1 Xiao Xu
A1 Toni Cheung
A1 J. Russell Burley
A1 Huikai Sun
A1 Louise Dickson
A1 Sean T. Murphy
A1 Nidhi Kaushal
A1 Steve Sheardown
A1 Jason Lawrence
A1 Yun Chen
A1 Darian Bartkowski
A1 Anne Kanta
A1 Joseph Russo
A1 Natalie Hosea
A1 Lee A. Dawson
A1 Stephen H. Hitchcock
A1 Mark B. Carlton
YR 2021
UL http://jpet.aspetjournals.org/content/377/3/407.abstract
AB 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.