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 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, BU08028 has high affinity at all opioid receptors and increased NOP receptor efficacy in vitro in the [35S]GTPγS binding assay, however 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 produces 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 likely due to mu receptor stimulation. It is likely that with BU08028, a partial agonist at both NOP and mu receptors, mu-mediated activity overpower 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.
- Received September 27, 2010.
- Revision received December 15, 2010.
- Accepted December 16, 2010.
- The American Society for Pharmacology and Experimental Therapeutics