Ligands for κ-Opioid and ORL1 Receptors Identified from a Conformationally Constrained Peptide Combinatorial Library

Becker, Jérôme A.J.; Wallace, Andrew; Garzon, Aaron; Ingallinella, Paolo; Bianchi, Elisabetta; Cortese, Riccardo; Simonin, Frédéric; Kieffer, Brigitte L.; Pessi, Antonello

doi:10.1074/jbc.274.39.27513

Cited by 103 publications

(75 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Buprenorphine, which was widely used as an analgesic molecule in newborns and infants, has also been shown to have ORL1 agonist activity (31). On the other hand, [Nphe 1 ]NC(1-13)NH 2 produces an antinociceptive action and potentiates morphineinduced analgesia (39) and a recent study described a new class of drugs with opioid agonist/ORL1 antagonist activities (53), thus opening new possibilities in the field of neuroprotection and analgesia in neonates.…”

Section: Figurementioning

confidence: 99%

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

View full text Add to dashboard Cite

IntroductionPeriventricular leukomalacia (PVL) is a hemispheric white-matter lesion that is often cystic and occurs most frequently in infants born before 32 weeks of gestation (1). PVL is the major cause of cerebral palsy among premature infants (2). Based on epidemiological and experimental studies, the pathophysiology of PVL appears to be multifactorial. It potentially involves the combined toxicity of hypoxic-ischemic insults, excess free radicals, maternal-fetal infection with increased cytokine production, and growth factor deficiency (1,(3)(4)(5)(6)(7)(8). Excess release of glutamate and the subsequent overactivation of the excitotoxic cascade could represent a common molecular pathway for several of these risk factors (6, 9).Findings from several experimental studies support this hypothesis. Newborn mice injected intracerebrally with ibotenate, a glutamate analog acting mainly on N-methyl-D-aspartate (NMDA) receptors, develop periventricular cystic white-matter lesions mimicking several aspects of human PVL (10). In this well characterized murine model, several drugs that interfere with the excitotoxic cascade have been shown to be neuroprotective (7,(11)(12)(13)(14) while proinflammatory cytokines (15) and iron (16) exacerbated ibotenateinduced white-matter lesions. In order to further understand the pathophysiology of the ibotenateinduced cystic lesions, we targeted the NMDA receptors thought to be present on white-matter glial cells. Newborn mice were injected intracerebrally with sense, antisense, or missense oligonucleotides specific for the NMDA R1 receptor subunit (P. Gressens, unpublished work). The sequences of the oligonucleotides were identical to those previously used by Wahlestedt et al. in an in vitro assay (17). In newborn mice, pretreatment with antisense oligonucleotides was neuroprotective while control sense oligonucleotides had no effect on the ibotenate-induced lesion. Unexpectedly, missense oligonucleotides, which were used as another control, induced a threefold reduction in the severity of the excitotoxic whitematter lesions. A search of databases with Basic Local Alignment Search Tool (BLAST) revealed that 12 successive nucleotides of the so-called "NMDA R1 missense oligonucleotide" were actually complementary to a triplicated motif of the murine nociceptin (NC) mRNA, suggesting that the blockade of NC production is neuroprotective in the ibotenate model. Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white-matter lesions, mimicking brain lesions that occur in human preterm infants. Nociceptin (NC), also called orphanin FQ, is the endogenous ligand of the opioid receptor-like 1 (ORL1) receptor and does not bind classical high-affinity opioid receptors. In the present study, administration of NC exacerbated ibotenate-induced white-matter lesions while coadministration of ibotenate with either of two NC antagonists reduced excitotoxic white-matter lesions by up to 64%. Neither ibotenate plus endomorphin I (a selective µ receptor agonist), nor ibot...

show abstract

Section: Figurementioning

confidence: 99%

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Laudenbach¹,

Calò²,

Guerrini³

et al. 2001

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…The following NOP ligands are currently available: i) small non peptide molecules, e.g. the agonist Ro 64-6198 [29] and the antagonists J-113397 [46] and SB-612111 [52]; ii) small peptides such as the hexapeptides Ac-RYYRWK-NH 2 and Ac-RYYRIK-NH 2 [19] and the pseudopentadapeptide III-BTD [2]; iii) a large series of N/ OFQ related peptides chemically modified for increasing agonist potency or for reducing or eliminating efficacy. Details about these three classes of NOP ligands can be found in recent review articles such as [53] and [3].…”

Section: Introductionmentioning

confidence: 99%

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

et al. 2007

View full text Add to dashboard Cite

Abstract[(pF)Phe 4 Aib 7 Arg 14 Lys 15 ]N/OFQ-NH 2 (UFP-112) has been designed as a novel ligand for the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) by combining into the same peptide different chemical modifications reported to increase N/OFQ potency. In vitro data obtained in the electrically stimulated mouse vas deferens demonstrated that UFP-112 behaved as a high potency (pEC 50 9.43) full agonist at the NOP receptor. UFP-112 effects were sensitive to the NOP antagonist UFP-101 but not to naloxone and no longer evident in tissues taken from NOP −/− mice. In vitro half life of UFP-112 in mouse plasma and brain homogenate was 2.6 and 3.5 fold higher than that of N/ OFQ. In vivo, in the mouse tail withdrawal assay, UFP-112 (1-100 pmol, i.c.v.) mimicked the actions of N/OFQ producing pronociceptive effects after i.c.v. administration and antinociceptive effects when given i.t; in both cases, UFP-112 was approx. 100 fold more potent than the natural peptide and produced longer lasting effects. UFP-112 also mimicked the hyperphagic effect of N/OFQ producing a bell shaped dose response curve with the maximum reached at 10 pmol. The hyperphagic effects of N/OFQ and UFP-112 were absent in NOP −/− mice. Equi-effective high doses of UFP-112 (0.1 nmol) and N/OFQ (10 nmol) were injected i.c.v. in mice and spontaneous locomotor activity recorded for 16 h. N/OFQ produced a clear inhibitory effect which lasted for 60 min while UFP-112 elicited longer lasting effects (> 6h). In conscious rats, UFP-112 (0.1 and 10 nmol/kg, i.v.) produced a marked and sustained decrease in heart rate, blood pressure, and urinary sodium excretion and a profound increase in urine flow. Collectively, these findings demonstrate that UFP-112 behaves in vitro and in vivo as a highly potent and selective ligand able to produce full and long lasting activation of NOP receptors.

show abstract

“…Constitutive activity has been reported for , ␦, and opioid receptors (Costa and Herz, 1989;Becker et al, 1999;Burford et al, 2000) as well as for some opioid receptor mutants (e.g., Huang et al, 2001). In addition, studies have demonstrated that chronic exposure to opioid agonists can increase constitutive signaling activity of , ␦, and opioid receptors (Costa and Herz, 1989;Becker et al, 1999;Liu and Prather, 2001).…”

mentioning

confidence: 98%

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

Sirohi

Dighe²,

Madia³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6␤-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone Ͼ naloxone Ͼ 6␤-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone Ͼ naloxone 6␤-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6␤-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6␤-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6␤-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

show abstract

Ligands for κ-Opioid and ORL1 Receptors Identified from a Conformationally Constrained Peptide Combinatorial Library

Cited by 103 publications

References 53 publications

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

Nociceptin/orphanin FQ exacerbates excitotoxic white-matter lesions in the murine neonatal brain

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

Contact Info

Product

Resources

About