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 μ, δ, κ, and NOP receptors. Among these, (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-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 [³⁵S]GTPγS 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 μ receptor stimulation. It is likely that with
BU08028, a partial agonist at both NOP and μ receptors, μ-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.