title: Peripherally Selective Cannabinoid 1 Receptor (CB1R) Agonists for the Treatment of Neuropathic Pain.
abstract: 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.
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Seltzman
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Craig
authors.initials: C
authors.lastname: Shiner
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Hirt
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Anne F
authors.initials: AF
authors.lastname: Gilliam
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Thomas
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Rangan
authors.initials: R
authors.lastname: Maitra
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Rod
authors.initials: R
authors.lastname: Snyder
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Black
authors.affiliation: Center for Drug Discovery, Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
authors.forename: Purvi R
authors.initials: PR
authors.lastname: Patel
authors.affiliation: Division of Oral Biology & Medicine, School of Dentistry, University of California , 10833 Le Conte Avenue, 63-078 CHS, Los Angeles, California 090095-1668, United States.
authors.forename: Yatendra
authors.initials: Y
authors.lastname: Mulpuri
authors.affiliation: Division of Oral Biology & Medicine, School of Dentistry, University of California , 10833 Le Conte Avenue, 63-078 CHS, Los Angeles, California 090095-1668, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Spigelman
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009437:Neuralgia / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D013329:Structure-Activity Relationship
chemical_list: D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2