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Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain
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
(<b>1</b>) 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