Alleviation of neuropathic pain by cannabinoids is limited by their central nervous system (CNS) side effects. Indole and indene compounds were engineered for high hCB1R affinity, peripheral selectivity, metabolic stability, and in vivo efficacy. An epithelial cell line assay identified candidates with <1% blood-brain barrier penetration for testing in a rat neuropathy induced by unilateral sciatic nerve entrapment (SNE). The SNE-induced mechanical allodynia was reversibly suppressed, partially or completely, after intraperitoneal or oral administration of several indenes. At doses that relieve neuropathy symptoms, the indenes completely lacked, while the brain-permeant CB1R agonist HU-210 (1) exhibited strong CNS side effects, in catalepsy, hypothermia, and motor incoordination assays. Pharmacokinetic findings of ∼0.001 cerebrospinal fluid:plasma ratio further supported limited CNS penetration. Pretreatment with selective CB1R or CB2R blockers suggested mainly CB1R contribution to an indene's antiallodynic effects. Therefore, this class of CB1R agonists holds promise as a viable treatment for neuropathic pain.

/pdf/peripherally-selective-cannabinoid-1-receptor-cb1r-agonists-fi2okgjaei.pdf

Detection of synthetic cannabinoids in urine by LC/MS/MS.

Citations

Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain

References

Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain

Related Papers (5)

Multidimensional LC/MS-MS Analysis of Synthetic Cannabinoids in Urine, Plasma, and Edibles

LC/ESI-MS/MS method for quantification of 28 synthetic cannabinoids in neat oral fluid and its application to preliminary studies on their detection windows.

Development of procedures for sreening for, identification and/or validated quantification of herbal drugs in blood or urine using GC-MS, LC-MS or LC-MS/MS

LC–MS/MS method for the quantitation of metabolites of eight commonly-used synthetic cannabinoids in human urine – An Australian perspective

Development and validation of a LC-MS/MS method for detection and quantification of 18 antidepressants in whole blood