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

• Published in: Journal of medicinal chemistry Vol. 59; no. 16; pp. 7525 - 7543
• Main Authors: Seltzman, Herbert H, Shiner, Craig, Hirt, Erin E, Gilliam, Anne F, Thomas, Brian F, Maitra, Rangan, Snyder, Rod, Black, Sherry L, Patel, Purvi R, Mulpuri, Yatendra, Spigelman, Igor
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 25-08-2016
• Subjects: Animals; CHO Cells; Cricetulus; Dogs; Dose-Response Relationship, Drug; Humans; Male; Molecular Structure; Neuralgia - drug therapy; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB2 - agonists; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00516

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.