title: BU08073 a buprenorphine analogue with partial agonist activity at μ-receptors in vitro but long-lasting opioid antagonist activity in vivo in mice.
abstract: OBJECTIVE
  Buprenorphine is a potent analgesic with high affinity at μ, δ and κ and moderate affinity at nociceptin opioid (NOP) receptors. Nevertheless, NOP receptor activation modulates the in vivo activity of buprenorphine. Structure activity studies were conducted to design buprenorphine analogues with high affinity at each of these receptors and to characterize them in in vitro and in vivo assays.
  
  
  METHODS
  Compounds were tested for binding affinity and functional activity using [(35) S]GTPγS binding at each receptor and a whole-cell fluorescent assay at μ receptors. BU08073 was evaluated for antinociceptive agonist and antagonist activity and for its effects on anxiety in mice.
  
  
  RESULTS
  BU08073 bound with high affinity to all opioid receptors. It had virtually no efficacy at δ, κ and NOP receptors, whereas at μ receptors, BU08073 has similar efficacy as buprenorphine in both functional assays. Alone, BU08073 has anxiogenic activity and produces very little antinociception. However, BU08073 blocks morphine and U50,488-mediated antinociception. This blockade was not evident at 1 h post-treatment, but is present at 6 h and remains for up to 3-6 days.
  
  
  CONCLUSIONS
  These studies provide structural requirements for synthesis of 'universal' opioid ligands. BU08073 had high affinity for all the opioid receptors, with moderate efficacy at μ receptors and reduced efficacy at NOP receptors, a profile suggesting potential analgesic activity. However, in vivo, BU08073 had long-lasting antagonist activity, indicating that its pharmacokinetics determined both the time course of its effects and what receptor-mediated effects were observed.
  
  
  BACKGROUND
  This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.
authors.affiliation: SRI International, Menlo Park, CA, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: Khroyan
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: W E
authors.initials: WE
authors.lastname: Polgar
authors.forename: G
authors.initials: G
authors.lastname: Cami-Kobeci
authors.forename: N
authors.initials: N
authors.lastname: Fotaki
authors.forename: S M
authors.initials: SM
authors.lastname: Husbands
authors.forename: L
authors.initials: L
authors.lastname: Toll
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016466:CHO Cells; D003412:Cricetulus; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008813:Mice, Inbred ICR; D009292:Narcotic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy / Q000503:physiopathology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; C000600933:BU08073; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D002047:Buprenorphine