title: A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects.
abstract: The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Δ(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2-yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N-arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPγS binding in mouse brain membranes and β-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Bogna M
authors.initials: BM
authors.lastname: Ignatowska-Jankowska
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Baillie
authors.affiliation: Department of Psychology, West Virginia University, Morgantown, WV, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Kinsey
authors.affiliation: Department of Psychology, West Virginia University, Morgantown, WV, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Crowe
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Sudeshna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Owens
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Imad M
authors.initials: IM
authors.lastname: Damaj
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Poklis
authors.affiliation: Research Triangle Institute, Research Triangle Park, NC, USA.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Wiley
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Matteo
authors.initials: M
authors.lastname: Zanda
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanato
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
authors.forename: Iain R
authors.initials: IR
authors.lastname: Greig
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Aron H
authors.initials: AH
authors.lastname: Lichtman
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ross
mesh_terms: D000494:Allosteric Regulation; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D063385:Cannabinoid Receptor Modulators / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002351:Carrageenan; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D013876:Thiophenes / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D018712:Analgesics, Non-Narcotic; D063385:Cannabinoid Receptor Modulators; D002351:Carrageenan; D007211:Indoles; D043884:Receptor, Cannabinoid, CB1; D013876:Thiophenes; D000099252:Fatty Acid Amide Hydrolases; C000604852:6-methyl-3-(2-nitro-1-(thiophen-2-yl)propyl)-2-phenyl-1H-indole