Antinociceptive analogs of orphanin FQ/nociceptin(1–11)

Mathis, John P.; Goldberg, Ira E.; Rossi, Grace C.; Leventhal, Liza; Pasternak, Gavril W.

doi:10.1016/s0024-3205(98)00358-0

Cited by 20 publications

(10 citation statements)

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“…This suggestion of OFQ/N receptor heterogeneity led us to explore the possibility that the truncated OFQ/N peptides might act through a subpopulation of OFQ/N receptors. Ear-lier studies from our group identified several analogs of OFQ/N(1-11) which might be suitable for binding studies (Mathis et al, 1998). We now report the identification of a novel binding site with high affinity for OFQ/N(1-11) in mouse brain.…”

Section: Introductionmentioning

confidence: 79%

“…In an effort to identify a OFQ/N(1-11) analog suitable for iodination and binding studies, we synthesized a number of derivatives in which tyrosine was replaced in positions 1, 10, or 11 (Mathis et al, 1998 10 ]OFQ/N(1-11) was not labeling an opioid site since OFQ/N(1-11), [Tyr 10 ]OFQ/N(1-11) and [IodoTyr 10 ] OFQ/N(1-11) display no appreciable affinity in traditional opioid receptor binding assays (Mathis et al, 1998).…”

Section: Resultsmentioning

confidence: 99%

“…Both peptides are pharmacologically active (Rossi et al, 1996King et al, 1997), with potencies similar to OFQ/N itself. Yet these truncated peptides have far lower affinities for the cloned orphan receptor and do not bind to opioid receptors (Mathis et al, 1997(Mathis et al, , 1998. Binding studies in mouse brain suggest OFQ/N receptor heterogeneity (Mathis et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Mathis

Goldberg

Letchworth

et al. 1999

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The presence of pairs of basic amino acids within the orphanin FQ/Nociceptin (OFQ/N) sequence has raised the possibility that truncated versions of the peptide might be physiologically important. OFQ/N(1-11) is pharmacologically active in mice, despite its poor affinity in binding assays (K(i) > 250 nM) for the OFQ/N receptor. Using an analog of OFQ/N(1-11), [(125)I][Tyr(10)]OFQ/N(1-11), we identified a high-affinity binding site (K(D) 234 pM; B(max) 43 fmol/mg protein) with a selectivity profile distinct from the OFQ/N receptor and all the traditional opioid receptors. This site had very high affinity for OFQ/N and its related peptides. The most striking differences between the new site and the OFQ/N receptor previously observed in brain were seen with traditional opioids. Dynorphin A analogs and alpha-neoendorphin competed with [(125)I][Tyr(10)]OFQ/N(1-11) binding in mouse brain with K(i) values below 10 nM, while naloxone benzoylhydrazone (K(i) 3.9 nM) labeled the [(125)I][Tyr(10)]OFQ/N(1-11) binding site as potently as many traditional opioid receptors. Several other opioids, including fentanyl, (-)cyclazocine, levallorphan, naltrindole, and diprenorphine, also displayed moderate affinities for this site. Finally, the [(125)I][Tyr(10)]OFQ/N(1-11) site had a unique regional distribution consistent with a distinct receptor. Thus, [(125)I][Tyr(10)]OFQ/N(1-11) labels a novel site in brain with a selectivity profile intermediate between that of either opioid or OFQ/N receptors.

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Section: Introductionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Mathis

Goldberg

Letchworth

et al. 1999

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“…The FT-IR and FT-Raman second-derivative spectra of all the investigated fragments reveal several components in the amide I region. Their wavenumbers and proposed assignments to the proper conformation are summarized in Table III (Table III) were calculated for FQ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) ]FQ (1-6), and FQ (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The bands at about 1674 and 1649 cm 21 are due to disordered/turn and a-helical conformations, respectively.…”

Section: Nociceptin and Its Natural And Specifically-modified Fragmentsmentioning

confidence: 99%

“…11,12 After cleavage by endogenous peptidases present in the spinal cord, nociceptin is converted to the shorter, bioactive fragments FQ (1)(2)(3)(4)(5)(6) and FQ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11); (fragments containing 1-6 and 1-11 residues from the FQ amino acid sequence, respectively). 13 FQ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) shows pharmacological activity in vivo similar to that of FQ, 14 while FQ (1-6) injected i.c.v. has a biphasic effect, i.e., analgesia followed by hyperalgesia in the hot-plate test, which is opposite to the sequence of effects induced by FQ.…”

Section: Introductionmentioning

confidence: 96%

Nociceptin and its natural and specifically‐modified fragments: Structural studies

et al. 2010

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The vibrational structures of Nociceptin (FQ), its short bioactive fragments, and specifically-modified [Tyr¹]FQ (1-6), [His¹]FQ (1-6), and [His(1,4)]FQ (1-6) fragments were characterized. We showed that in the solid state, all of the aforementioned peptides except FQ adopt mainly turn and disordered secondary structures with a small contribution from an antiparallel β-sheet conformation. FQ (1-11), FQ (7-17) [His¹]FQ (1-6), and [His(1,4)]FQ (1-6) have an α-helical backbone arrangement that could also slightly influence their secondary structure. The adsorption behavior of these peptides on a colloidal silver surface in an aqueous solution (pH = ∼8.3) was investigated by means of surface-enhanced Raman scattering (SERS). All of the peptides, excluding FQ (7-17), chemisorbed on the colloidal silver surfaces through a Phe⁴ residue, which for FQ, FQ (1-11), FQ (1-6), [Tyr¹]FQ (1-6), and [His¹]FQ (1-6) lies almost flat on this surface, while for FQ (1-13) and FQ (1-13)NH₂ adopts a slightly tilted orientation with respect to the surface. The Tyr¹ residue in [Tyr¹]FQ (1-6) does not interact with the colloidal silver surface, suggesting that the Tyr¹ and Phe⁴ side chains are located on the opposite sides of the peptide backbone, which can be also true for His¹ and Phe⁴ in [His¹]FQ (1-6). The lone pair of electrons on the oxygen atom of the ionized carbonyl group of FQ (1-13) and FQ (7-17) appears to be coordinated to the colloidal silver nanoparticles, whereas in the case of the remaining peptides, it only assists in the adsorption process, similar to the --NH⁴ group. We also showed that upon adsorption, the secondary structure of these peptides is altered.

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Autoradiographic localization of125I[Tyr14]orphanin FQ/nociceptin and125I[Tyr10]orphanin FQ/nociceptin(1-11) binding sites in rat brain

et al. 2000

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The endogenous ligand for the orphan opioid receptor, orphanin FQ/nociceptin (OFQ), has recently been characterized. The OFQ peptide sequence contains paired basic amino acids, suggesting the possibility of posttranslational processing to a peptide containing the first 11 amino acids of the OFQ peptide. This peptide has been reported in the brain and it has a unique pharmacology. In the present study, we compared the autoradiographic distribution of (125)I[Tyr(14)]OFQ and (125)I[Tyr(10)]OFQ(1-11) in coronal rat brain sections. Nonspecific binding was defined with unlabeled OFQ or OFQ(1-11), respectively. Both radioligands demonstrated high levels of specific binding (>95% of total binding), with no appreciable binding in white matter areas with either ligand. (125)I[Tyr(14)]OFQ binding was widely distributed throughout the rat brain. In contrast, (125)I[Tyr(10)]OFQ(1-11) binding was more restricted. The highest (125)I[Tyr(14)]OFQ binding levels measured in this study were found in the locus coeruleus, an area which contained very low (125)I[Tyr(10)]OFQ(1-11) binding. Both ligands labeled the cortex, hippocampus and amygdala. In the thalamus, (125)I[Tyr(14)]OFQ binding was prominent in most nuclei, whereas (125)I[Tyr(10)]OFQ(1-11) binding was restricted to the midline thalamus. (125)I[Tyr(14)]OFQ binding was heavy in the suprachiasmatic hypothalamus, and moderate in other hypothalamic nuclei. (125)I[Tyr(10)]OFQ(1-11) binding in the hypothalamus, however, was present mainly in the ventromedial hypothalamic nucleus. Lower binding levels of both ligands were found in the caudate putamen. The distinct autoradiographic patterns of these two ligands are consistent with different binding sites, which might help explain their different functional activities.

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Antinociceptive analogs of orphanin FQ/nociceptin(1–11)

Cited by 20 publications

References 20 publications

Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Identification of a high-affinity orphanin FQ/nociceptin(1-11) binding site in mouse brain

Nociceptin and its natural and specifically‐modified fragments: Structural studies

Autoradiographic localization of125I[Tyr14]orphanin FQ/nociceptin and125I[Tyr10]orphanin FQ/nociceptin(1-11) binding sites in rat brain

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