Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists

From our NETSseq-derived human brain transcriptomics
data, we identified
GPR55 as a potential molecular target for the treatment of motor symptoms
in patients with Parkinson’s disease. From a high-throughput
screen, we identified and optimized agonists with nanomolar potency
against both human and rat GPR55. We discovered compounds with either
strong or limited β-arrestin signaling and receptor desensitization,
indicating biased signaling. A compound that showed minimal GPR55
desensitization demonstrated a reduction in firing frequency of medium
spiny neurons cultured from rat striatum but did not reverse motor
deficits in a rat hypolocomotion model. Further profiling of several
desensitizing and non-desensitizing lead compounds showed that they
are selective over related cannabinoid receptors CB1 and
CB2 and that unbound brain concentrations well above the
respective GPR55 EC50 can be readily achieved following
oral administration. The novel brain-penetrant GPR55 agonists disclosed
can be used to probe the role of this receptor in the brain.