Discovery and Characterization of Novel CNS-Penetrant GPR55 Agonists.
Richard C HewerLouisa A ChristieKevin J DoyleXiao XuMaxine J RobertsLouise DicksonToni CheungDavid H CadwalladrPhilip PickfordMartin TeallJustin A C PowellSteven SheardownLakshminarayana NarayanaNicola L BriceLee A DawsonMark CarltonRoland W BürliPublished in: Journal of medicinal chemistry (2023)
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 CB 1 and CB 2 and that unbound brain concentrations well above the respective GPR55 EC 50 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.
Keyphrases
- high throughput
- fatty acid
- single cell
- resting state
- endothelial cells
- white matter
- oxidative stress
- functional connectivity
- cerebral ischemia
- traumatic brain injury
- spinal cord
- small molecule
- blood brain barrier
- brain injury
- binding protein
- physical activity
- subarachnoid hemorrhage
- spinal cord injury
- machine learning
- replacement therapy
- single molecule
- fluorescent probe