Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

Hruby, Victor J.; Agnes, Richard S.; Davis, Peg; Ma, Shou-Wu; Lee, Y.S; Vanderah, Todd W.; Lai, Josephine; Porreca, Frank

doi:10.1016/s0024-3205(03)00390-4

Cited by 41 publications

(41 citation statements)

References 11 publications

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“…In previous studies investigating calcitonin gene-related peptide (59) and opioid agonists (60), minor modifications in amino acid sequence have resulted in dramatic differences in ligand binding properties. Despite these findings, considerable efforts are still required to obtain a full understanding of the structure-activity relationship between -TIA and the ␣ 1 -AR subtypes.…”

Section: Discussionmentioning

confidence: 99%

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Chen

Rogge

Hague

et al. 2004

Journal of Biological Chemistry

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The 19-amino acid conopeptide ( -TIA) was shown previously to antagonize noncompetitively ␣ 1B -adrenergic receptors (ARs). Because this is the first peptide ligand for these receptors, we compared its interactions with the three recombinant human ␣ 1 -AR subtypes (␣ 1A , ␣ 1B , and ␣ 1D ). Radioligand binding assays showed that -TIA was 10-fold selective for human ␣ 1B -over ␣ 1A -and ␣ 1D -ARs. As observed with hamster ␣ 1B -ARs, -TIA decreased the number of binding sites (B max ) for human ␣ 1B -ARs without changing affinity (K D ), and this inhibition was unaffected by the length of incubation but was reversed by washing. However, -TIA had opposite effects at human ␣ 1A -ARs and ␣ 1D -ARs, decreasing K D without changing B max , suggesting it acts competitively at these subtypes. -TIA reduced maximal NE-stimulated [ 3 H]inositol phosphate formation in HEK293 cells expressing human ␣ 1B -ARs but competitively inhibited responses in cells expressing ␣ 1A -or ␣ 1D -ARs. Truncation mutants showed that the amino-terminal domains of ␣ 1B -or ␣ 1D -ARs are not involved in interaction with -TIA. Alanine-scanning mutagenesis of -TIA showed F18A had an increased selectivity for ␣ 1B -ARs, and F18N also increased subtype selectivity. I8A had a slightly reduced potency at ␣ 1B -ARs and was found to be a competitive, rather than noncompetitive, inhibitor in both radioligand and functional assays. Thus -TIA noncompetitively inhibits ␣ 1B -ARs but competitively inhibits the other two subtypes, and this selectivity can be increased by mutation. These differential interactions do not involve the receptor amino termini and are not because of the charged nature of the peptide, and isoleucine 8 is critical for its noncompetitive inhibition at ␣ 1B -ARs.

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Section: Discussionmentioning

confidence: 99%

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Chen

Rogge

Hague

et al. 2004

Journal of Biological Chemistry

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“…We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure [14][15][16] and in vivo assay results of these ligands demonstrated the validity of our working hypothesis. 13 Herein we describe our efforts to find whether in such design of ligands to interact with more than one receptor, it is possible to design ligands with overlapping pharmacophores for opioid and MC receptors that eventually will be of benefit for rational drug design for the treatment of pain.…”

Section: Introductionmentioning

confidence: 87%

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

et al. 2008

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We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6‐dimethyltyrosine (Dmt)‐1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic), and a small molecule for the MC receptor, Tic‐DPhe(p‐Cl)‐piperidin‐4‐yl‐N‐phenyl‐propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP‐γ‐S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC‐3 receptor rather than at the MC‐5 receptor. A study of the structure‐activity relationships demonstrated that the residues in positions 2, 3, and the C‐terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 433–438, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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“…[172][173][174][175][176][177] These findings prompted the attempts to develop new compounds possessing characteristics of agonists toward the MOR and of antagonists toward CCK or NK receptors, in the same sequence, to improve the effectiveness of the antinociception and eliminate adverse effects. The design of bifunctional analogues with overlapping pharmacophore elements at opioid receptor and CCK or NK receptor led to the expected peptide compounds: Tyr-D-Nle-Gly-Trp-Nle-Asp-Phe-NH 2 , Tyr-D-Phe-Gly-D-Trp-NMeNle-AspPhe-NH 2 , Tyr-D-Ala-Gly-D-Trp-NMeNle-Asp-Phe-NH 2 , and chimeric derivative AA501 (N 0 (Tyr-D-Ala-Gly-Phe), N 00 (Z-Trp) hydrazide, Z 5 benzyloxycarbonyl), etc., [176][177][178] which shows quite good m-/d-angonist activities in vitro, and high CCK-2 receptor binding affinity, CCK antagonist activity. However, efforts to connect EM sequences to these CCK/NK pharmacophores has not yet been reported and need to be proved that whether it will render a effective way to lower propensity of tolerance and physical dependence of the endomorphin native tetrapeptides.…”

Section: B Analogues With Mixed L-agonist/ckk (Nk)-antagonist Activitymentioning

confidence: 99%

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

Liu

Wang

2011

Medicinal Research Reviews

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The application of endomorphins as clinical available analgesic drugs has been impeded by their relatively poor receptor selectivity compared with alkaloid analgesics, rapid degradation in vivo, inefficient to penetrate the blood-brain barrier (BBB), and undesirable or toxic effects, such as acute tolerance and physical dependence, respiratory depression, and inhibition of gastrointestinal motility. Extensive studies have been performed so far striving to conquer these problems. In this article we review and discuss conformational and topographical modifications of the peptide amide bond and amino acid side groups to attain the most appropriate receptor binding affinity and high receptor selectivity; diverse strategies such as insertion of unnatural amino acids, covalent or noncovalent constraints as well as cyclization of linear peptides to enhance the enzymatic stability; designing of peptidomimetic ligands, glycopeptides, and N-terminal amidinationed analogues (such as incorporating guanidine into endomorphins) to penetrate the BBB. Also, several pertinent examples of bivalent and/or multivalent (such as mixed µ-agonist/δ-antagonist profile) compounds are discussed based on the existing literature and current data intending to give an insight into the development of opioid peptides expressing low tendency to produce acute tolerance and physical dependence.

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Design of novel peptide ligands which have opioid agonist activity and CCK antagonist activity for the treatment of pain

Cited by 41 publications

References 11 publications

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Subtype-selective Noncompetitive or Competitive Inhibition of Human α1-Adrenergic Receptors by ρ-TIA

Opioid and melanocortin receptors: Do they have overlapping pharmacophores?

Endomorphins: potential roles and therapeutic indications in the development of opioid peptide analgesic drugs

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