title: Characterization of the complex morphinan derivative BU72 as a high efficacy, long-lasting mu-opioid receptor agonist.
abstract: The development of buprenorphine as a treatment for opiate abuse and dependence has drawn attention to opioid ligands that have agonist actions followed by long-lasting antagonist actions. In a search for alternatives to buprenorphine, we discovered a bridged pyrrolidinomorphinan (BU72). In vitro, BU72 displayed high affinity and efficacy for mu-opioid receptors, but was also a partial delta-opioid receptor agonist and a full kappa-opioid receptor agonist. BU72 was a highly potent and long-lasting antinociceptive agent against both thermal and chemical nociception in the mouse and against thermal nociception in the monkey. These effects were prevented by mu-, but not kappa- or delta-, opioid receptor antagonists. Once the agonist effects of BU72 had subsided, the compound acted to attenuate the antinociceptive action of morphine. BU72 is too efficacious for human use but manipulation to reduce efficacy could provide a lead to the development of a treatment for opioid dependence.
authors.affiliation: Department of Pharmacology, University of Michigan, 1301 Medical Science Res. Bldg III, Ann Arbor, MI 48109, USA.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Neilan
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: Simon
authors.initials: S
authors.lastname: Breeden
authors.forename: M C Holden
authors.initials: MC
authors.lastname: Ko
authors.forename: Mario D
authors.initials: MD
authors.lastname: Aceto
authors.forename: John W
authors.initials: JW
authors.lastname: Lewis
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002047:Buprenorphine / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013997:Time Factors; D014316:Tritium; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000700:Analgesics; C496287:BU72 compound; D009019:Morphinans; D011758:Pyrroles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002047:Buprenorphine; D009020:Morphine