Comparison of the Antinociceptive and Antirewarding Profiles of Novel Bifunctional Nociceptin Receptor/μ-Opioid Receptor Ligands: Implications for Therapeutic Applications

Abstract

The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the -opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphineinduced CPP.

Differential Effects of Nociceptin/Orphanin FQ (NOP) Receptor Agonists in Acute versus Chronic Pain: Studies with Bifunctional NOP/μ Receptor Agonists in the Sciatic Nerve Ligation Chronic Pain Model in Mice

“…In a previous study, we have shown that SR14150 produces antinociception in the tail-flick assay in animals that are not in chronic pain (Toll et al, 2009). Likewise, here we report that SR14150 produces an increase in tail-flick latency in SNL animals.…”

“…Morphine, SR14150, and SR16835 produced antinociceptive effects, so in follow-up experiments, animals received a pretreatment of 1 mg/kg opioid antagonist naloxone or a pretreatment of 10 mg/kg NOP receptor antagonist SB-612111 (Zaratin et al, 2004) to determine whether drug-mediated effects were due to opioid or NOP receptor activity. The dose of naloxone chosen has been shown to reverse the effects of morphine, and the dose of SB-612111 was chosen on the basis of our previous experiments (Khroyan et al, 2007b;Toll et al, 2009). The antagonists were given 10 min before the injection of morphine, SR14150, or SR16835.…”

“…Bifunctional compounds with both NOP and -opioid receptor agonist activity, such as 1- (1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16435) and 1-(1-cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and even the opioid partial agonist buprenorphine, have significant -mediated antinociceptive activity in the tail-flick assay, which is blocked by naloxone rather than an NOP receptor antagonist. In fact, the activity of these compounds is potentiated by the NOP receptor antagonist (Ϫ)-cis- 1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111), suggesting that the NOP receptor agonist activity of these compounds is attenuating its -agonist activity (Khroyan et al, 2007a(Khroyan et al, , 2009aToll et al, 2009).…”

The First Universal Opioid Ligand, (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): Characterization of the In Vitro Profile and In Vivo Behavioral Effects in Mouse Models of Acute Pain and Cocaine-Induced Reward

“…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 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.…”

“…However, the optimum profile of and NOP receptor affinity and/or efficacy for an optimum balance of analgesia to antagonism, reward to reward attenuation, and locomotor activation to sedation for a useful therapeutic profile cannot be predicted. We have demonstrated that such mixed NOP/ compounds can be developed with significant antinociceptive activity and greatly reduced reward, but to attenuate reward in a traditional NOP receptor nonopioid small-molecule pharmacophore (see Zaveri et al, 2005), the NOP component must overshadow the component with respect to affinity and/or efficacy (Khroyan et al, 2007;Toll et al, 2009). This is not the case with buprenorphine, in which the affinity is far greater than the NOP receptor affinity.…”