title: BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism.
abstract: In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5beta,7beta,3',5']-pyrrolidino-2'[S]-phenyl-7alpha-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPgammaS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK. s.m.husbands@bath.ac.uk
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: Claire L
authors.initials: CL
authors.lastname: Neilan
authors.forename: Jillian
authors.initials: J
authors.lastname: Broadbear
authors.forename: Peter
authors.initials: P
authors.lastname: Grundt
authors.forename: Simon
authors.initials: S
authors.lastname: Breeden
authors.forename: Mario D
authors.initials: MD
authors.lastname: Aceto
authors.forename: James H
authors.initials: JH
authors.lastname: Woods
authors.forename: John W
authors.initials: JW
authors.lastname: Lewis
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D019342:Acetic Acid; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001952:Bridged-Ring Compounds / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006358:Hot Temperature / Q000009:adverse effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000737:chemistry / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000209:etiology / Q000517:prevention & control; D010147:Pain Measurement; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
chemical_list: C501104:17-cyclopropylmethyl-3-hydroxy-(5beta,7beta,3',5')-pyrrolidino-2'(S)-phenyl-7alpha-methyl-6,14-endoetheno morphinan; D000700:Analgesics; D001575:Benzomorphans; D001952:Bridged-Ring Compounds; D009019:Morphinans; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C027248:bremazocine; D019342:Acetic Acid