title: Cannabinoid CB1 receptor as a target for chlorpyrifos oxon and other organophosphorus pesticides.
abstract: Binding of the endocannabinoid anandamide or of Delta(9)-tetrahydrocannabinol to the agonist site of the cannabinoid receptor (CB1) is commonly assayed with [3H]CP 55,940. Potent long-chain alkylfluorophosphonate inhibitors of agonist binding suggest an additional, important and closely-coupled nucleophilic site, possibly undergoing phosphorylation. We find that the CB1 receptor is also sensitive to inhibition in vitro and in vivo by several organophosphorus pesticides and analogs. Binding of [3H]CP 55,940 to mouse brain CB1 receptor in vitro is inhibited 50% by chlorpyrifos oxon at 14 nM, chlorpyrifos methyl oxon at 64 nM and paraoxon, diazoxon and dichlorvos at 1200-4200 nM. Some 15 other organophosphorus pesticides and analogs are less active in vitro. The plant defoliant tribufos inhibits CB1 in vivo, without cholinergic poisoning signs, by 50% at 50 mg/kg intraperitoneally with a recovery half-time of 3-4 days, indicating covalent derivatization. [3H-ethyl]Chlorpyrifos oxon may be suitable for radiolabeling and characterization of this proposed nucleophilic site.
authors.affiliation: Department of Environmental Science, Policy and Management, Environmental Chemistry and Toxicology Laboratory, University of California, Berkeley, CA 94720-3112, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Quistad
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.forename: Susan E
authors.initials: SE
authors.lastname: Sparks
authors.forename: Yoffi
authors.initials: Y
authors.lastname: Segall
authors.forename: John E
authors.initials: JE
authors.lastname: Casida
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators; D004390:Chlorpyrifos / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity*; D003678:Defoliants, Chemical / Q000378:metabolism; D007306:Insecticides / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000378:metabolism / Q000633:toxicity; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000633:toxicity; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D003678:Defoliants, Chemical; D007306:Insecticides; D009281:Naphthalenes; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C006845:butonate; C009618:O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate; C065365:CP 55244; D004390:Chlorpyrifos