title: Bivalent ligands that target μ opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance.
abstract: Given that μ opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both μ agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota , Minneapolis, Minneapolis 55455, United States.
authors.forename: Morgan
authors.initials: M
authors.lastname: Le Naour
authors.forename: Eyup
authors.initials: E
authors.lastname: Akgün
authors.forename: Ajay
authors.initials: A
authors.lastname: Yekkirala
authors.forename: Mary M
authors.initials: MM
authors.lastname: Lunzer
authors.forename: Mike D
authors.initials: MD
authors.lastname: Powers
authors.forename: Alexander E
authors.initials: AE
authors.lastname: Kalyuzhny
authors.forename: Philip S
authors.initials: PS
authors.lastname: Portoghese
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D015195:Drug Design; D004361:Drug Tolerance; D004705:Endocytosis / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008024:Ligands; D008297:Male; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D015394:Molecular Structure; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D008024:Ligands; D043884:Receptor, Cannabinoid, CB1; D017450:Receptors, Opioid, mu