yl)piperidinl-4-yl)-indolin-2-one (SR16835), which are not in the oripavine family, but bind with greater affinity to the NOP receptor, also have -mediated antinociceptive activity that is attenuated by the NOP component (Khroyan et al., 2009). Like- wise, buprenorphine enhances alcohol consumption at low doses, presumably through opioid receptors, but reduces alcohol consumption at higher doses. This reduction in alcohol consumption is blocked by the NOP receptor antagonist [Nphe 1 ,Arg 14 ,Lys 15 ]nociceptin-NH 2 (UFP-101), suggesting that the buprenorphine-induced reduction in alcohol consumption is caused by activation of NOP receptors (Ciccocioppo et al., 2007). An NOP-mediated reduction in CPP and self-administration of a variety of abused drugs by N/OFQ is already well documented (Murphy et al., 1999; Kotlin ́ ska et al., 2002; Ciccocioppo et al., 2003; Zhao et al., 2003). Therefore, it is possible that increasing the NOP agonist efficacy in buprenorphine, or other opioid ligands, may produce an effective nonaddicting analgesic and may be more efficacious than buprenorphine for drug abuse pharmacotherapy.
The buprenorphine analog BU08028 was designed to have increased affinity and efficacy at the NOP receptors. BU08028 is the first reported “universal opioid ligand” that binds with high affinity (under 10 nM) to each of the receptors in the opioid receptor family. BU08028 is almost 10 times more potent at NOP receptors than buprenorphine and also has higher functional efficacy at NOP compared with buprenorphine in vitro (Table 2). Because BU08028 has similar receptor activity to buprenorphine but increased NOP activity, we expect diminished -receptor-mediated effects such as antinociceptive activity, tolerance development, and reward. In acute antinociception assays, BU08028 seems less potent than buprenorphine, showing virtually no antinociceptive activity at 0.1 mg/kg and little activity at 0.3 mg/kg (Fig. 2), possibly suggesting NOP-mediated suppression of -mediated antinociception. However, the antinociceptive activity of BU08028 is potentiated only by the NOP receptor antagonist SB612111 at higher doses of BU08028, suggesting NOP receptor agonist activity has little or no dis- cernable effect on antinociception at low doses of BU08028.
Alternatively, the lack of antinociceptive activity at low doses might suggest that the higher logP of BU08028 is hindering its access to the central nervous system. Even though the partial agonist activity of BU08028 at receptors in vitro is similar to that of buprenorphine, the dose-response curve of BU08028 for antinociception is much steeper than that of buprenorphine, where the higher doses of BU08028 produced near maximal effects. As demonstrated in many reports, the dose-response curve for buprenorphine is very shallow, never approaching 100% MPE (Cowan et al., 1977; Ide et al., 2004).
In addition, animals dosed with BU08028 exhibit a very profound Straub tail (T. Khroyan, unpublished observation), indicative of -like excitatory activity, and an obvious increase in locomotor activity, also a -mediated effect in mice (Cowan et al., 1977). BU08028 produces antinociceptive effects that are longer- lasting than buprenorphine, consistent with BU08028’s higher logP. BU08028 antinociception is still strongly evident 24 h postinjection with virtually 100% activity remaining at 10 mg/kg, whereas buprenorphine antinociceptive activity is no longer evident at this later time (Fig. 2). Furthermore, it was anticipated that a compound with higher NOP efficacy, similar to the mixed NOP/ agonist SR16435, would likely have a reduced tolerance development (Khroyan et al., 2007). However, as shown in Fig. 5, administration of BU08028 over 9 days resulted in tolerance to its antinociceptive effects, similar to that seen with morphine and buprenorphine.From these experiments it is evident that BU08028 produces a very long-lasting antinociceptive effect, but tolerance to this effect develops at a similar pace compared with the parent compound buprenorphine. Initial assessment of the rewarding effects of BU08028 was conducted using the one-trial PC paradigm with a 48-h period between drug and vehicle sessions (Fig. 6). This behavioral protocol was used to avoid any interference with the long- lasting effects of BU08028.
Similar to morphine, BU08028 produced CPP. BU08028 was also directly compared with its parent compound buprenorphine using this same protocol. Buprenorphine produced an inverted U-shaped dose-response curve where the 3 mg/mg dose produced a significant CPP and 1 and 10 mg/kg did not, a phenomenon that has previously been observed in rats (Brown et al., 1991; Rowlett et al., 1994). In mice, CPP to buprenorphine has been reported after repeated injections at the 3 mg/kg dose, whereas one-trial conditioning with this dose did not result in CPP (Marquez et al., 2007, 2008). Using the more common repeated-injection PC protocol, BU08028 also produced CPP after four drug pairings, when drug sessions were not separated by 48 h (Fig. 7). Apparently, the effect of BU08028, with respect to “reward,” is not as long- lasting as its antinociceptive effect, lasting less than 24 h, being associated only with the drug-paired compartment and not in- terfering with the production of a CPP. 18,19-Dehydrobu- prenorphine (HS 599), a didehydro derivative of buprenorphine that is also long-lasting, did not produce CPP in the traditional PC training regimen (Lattanzi et al., 2001). It is possible that, unlike BU08028, HS 599 may have longer-lasting effects that influence the development of CPP, and that the drug effects could have carried over to the vehicle session. In any case, the present findings show that BU08028 produces CPP alone and suggest that its NOP agonist activity is not attenuating its receptor-mediated behavior with respect to antinociception, tolerance development, or reward.
Although buprenorphine is approved for maintenance for heroin addiction, it has been considered as a potential pharmacotherapy for other abused drugs. Previous research has examined the effects of buprenorphine on cocaine-induced behaviors. Chronic buprenorphine administration can decrease cocaine intake during self-administration, drug-in- duced reinstatement of extinguished cocaine seeking, and cocaine-induced locomotor activity (Sorge et al., 2005; Sorge and Stewart, 2006; Placenza et al., 2008). In the PC paradigm, buprenorphine has been reported to both attenuate and potentiate cocaine-induced CPP (Brown et al., 1991; Kosten et al., 1991). These discrepant findings are probably caused by the experimental parameters including the drug regimen used. We were hoping that BU08208 would reduce cocaine-induced CPP. Not surprisingly, however, because BU08028 produced CPP, it was unable to attenuate cocaine- induced CPP.
The goal of this project was to synthesize and characterize compounds with significant NOP receptor activity to supple- ment (and potentially ␦ and ) activity found in the buprenorphine scaffold. The behavioral results obtained with BU08028 can also be compared with other bifunctional /NOP receptor ligands that we have characterized previously. We have demonstrated previously that SR14150 and SR16435, both with high affinity and partial agonist activity at NOP and receptors, have antinociceptive activity that is inhibited by naloxone and potentiated by the NOP receptor antagonist SB612111 (Khroyan et al., 2009; Toll et al., 2009). SR16435, which has an in vitro profile strikingly similar to BU08028, produces antinociception and CPP, indicating that, like BU08028, the NOP component is not sufficient to block the rewarding effect of the component. It is interesting to note that SR16435 has one behavioral feature diamet- rically opposed to that of BU08028. Although BU08028 causes a large increase in locomotor activity, SR16435 does the opposite, resulting in reduced activity levels, a behavior attributed to NOP receptor activation.
This difference in global activity observed with SR16435 and BU08028 is diffi- cult to explain because these compounds have a similar in vitro profile with respect to NOP, , and receptors, but suggest once again that the -mediated activities are strongly represented in BU08028. Alternately, it is possible that the very weak ␦ component of BU08028, which is not present at all in SR16435, might contribute to the increased global activity seen in BU08028. As we have shown previously, it is possible to overcome potential -, -, and ␦ -mediated behavior by increasing the relative NOP activity of a compound. For example, we have shown that SR14150, which has increased NOP affinity and is 20-fold selective for NOP over receptors, is not rewarding on its own (Toll et al., 2009). To go one step further, SR16835 is a full agonist at NOP receptors and a weak partial agonist at receptors. This compound is not analgesic on its own and is able to attenuate morphine CPP (Toll et al., 2009). To- gether, all of these data suggest that the balance of NOP and components of mixed-profile compounds such as these can have significant impact in modulating the antinociceptive and rewarding aspects of the compounds. With BU08028, which is a partial agonist at both NOP and receptors, -mediated activity masks effects that could be mediated by the NOP receptor. It is possible that a different buprenorphine analog with high affinity at all the opioid receptors but with full agonist activity at NOP may counteract other traditional opioid-mediated effects such as reward and antinociception.
Plus given what we know about bupe and its pharmacology... makes me wonder what the effect of the nor-compound of this drug would be? Perhaps a (more) potent MOR ligand like norbupe?
