The first universal opioid ligand, (2S)-2- (5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydro xy-6-methoxymorphinan-7-yl -3,3-dimethylpentan-2-ol (BU08028): Characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward

T V Khroyan, W E Polgar, Gerta Cami-Kobeci, Stephen M Husbands, N T Zaveri, L Toll

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Certain behavioral features of buprenorphine, including a bell-shaped curve for antinociception and attenuation of alcohol consumption, are thought to be mediated by activation of nociceptin/orphanin FQ peptide (NOP) receptors, despite moderate affinity and low efficacy at NOP receptors. We hypothesized that ligands with buprenorphine's physical properties, but possessing increased NOP receptor affinity and efficacy, would improve the profile as a drug abuse medication and reduce addiction liability. Using this strategy, we designed several compounds with universally high affinity, i.e., less than 10 nM at mu, delta, kappa, and NOP receptors. Among these, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano3- hydroxy-6-methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028) has high affinity at all opioid receptors and increased NOP receptor efficacy in vitro in the [S-35]GTP gamma S binding assay, however, while still being a partial agonist. In vivo, BU08028 was evaluated in an acute thermal antinociception assay, for its ability to induce conditioned place preference (CPP), and for its effect on cocaine-induced CPP. BU08028 is a very potent long-lasting analgesic. It produces an increase in locomotor activity and a significant CPP. As a pretreatment to cocaine, BU08028 does not alter cocaine CPP but causes a further increase in cocaine-induced locomotor activity. The analgesic, rewarding, and stimulant effects are probably caused by mu receptor stimulation. It is likely that with BU08028, a partial agonist at both NOP and mu receptors, mu-mediated activity overpowers NOP-mediated effects. Thus, it is possible that a different buprenorphine analog that is a universal high-affinity opioid ligand but with "full agonist" activity at NOP may counteract traditional opioid-mediated effects such as antinociception and reward.
Original languageEnglish
Pages (from-to)952-961
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume336
Issue number3
DOIs
Publication statusPublished - Mar 2011

Fingerprint Dive into the research topics of 'The first universal opioid ligand, (2S)-2- (5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydro xy-6-methoxymorphinan-7-yl -3,3-dimethylpentan-2-ol (BU08028): Characterization of the in vitro profile and in vivo behavioral effects in mouse models of acute pain and cocaine-induced reward'. Together they form a unique fingerprint.

Cite this