Partial Retro−Inverso, Retro, and Inverso Modifications of Hydrazide Linked Bifunctional Peptides for Opioid and Cholecystokinin (CCK) Receptors

Lee, Yeon Sun; Agnes, Richard S.; Davis, Peg; Ma, Shou-Wu; Badghisi, Hamid; Lai, Josephine; Porreca, Frank; Hruby, Victor J.

doi:10.1021/jm061268p

Cited by 27 publications

(14 citation statements)

References 18 publications

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“…In contrast, the D and RI isomers resist degradation remaining completely intact even after 4 h of digestion (Figure ). This is consistent with previous work that peptides containing D ‐amino acids, in either D or RI formats, are poor substrates for proteases and resist degradation .…”

Section: Resultsmentioning

confidence: 99%

“…An alternate approach for peptide stabilization is through retro‐inversion in which the peptide sequence is reversed and the chirality of each amino acid is inverted . Retro‐inversed (RI) peptides are anticipated to present the same three‐dimensional positioning of side chains as their L‐counterparts, allowing them to retain biological function but with resistance to proteolytic degradation as a consequence of the D‐amino acids . The applicability of retro‐inversion to a particular peptide likely depends on a number of factors including the conformational flexibility of the peptide, whether the association with the biological effector is dominated by interactions with peptide side‐chain or main‐chain groups, as well as the ability of the cognate receptor to induce bioactive conformations in a template‐mediated fashion; i.e.…”

Section: Introductionmentioning

confidence: 99%

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Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Krasniqi

Scruten

Piller

et al. 2012

Journal of Peptide Science

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Peptide modifications that improve pharmacological properties are of considerable therapeutic importance. Here we consider the retro (R), inversed (D) and retro-inversed (RI) isomers of glucagon with respect to structure, stability, toxicity and biological activity. Biologically, RI-glucagon demonstrated comparable in vivo activity as L-glucagon with respect to magnitude and duration of blood sugar elevation following i.p. administration to mice. Structurally, the isomers were investigated through circular dichroism (CD) and nanopore analysis. CD demonstrated a conserved potential for formation of secondary structure, which was independent of the direction of the peptide (L vs R; D vs RI) as well as formation of symmetry-related structures for the chiral isomers (L vs D; R vs RI). CD, therefore, discriminated chiral but not directional isomers. Nanopore analysis, which depends on interaction of the peptides with chiral pores, discriminated all four isomers on the basis of unique signatures of bumping and translocation. Nanopore analysis offered greater opportunity than CD to discriminate the isomers although neither technique provided a definitive biomarker of biological activity. Functionally, the R and RI isomers resist proteolytic degradation and none of the isomers possess hemolytic activity or cellular toxicity. Collectively, this investigation highlights the potentials and limitations of CD and nanopore analysis for investigation of peptide isomers as well as offering insight into the structural criteria to mimic peptide biological activity. For this example, retro-inversion, through undefined contributions of increased stability and maintained biological activity, was best suited to mimic the biological activity of the parent peptide.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Krasniqi

Scruten

Piller

et al. 2012

Journal of Peptide Science

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“…However, it was not demonstrated that this compound behaved as an antagonist against CCK. Partial retro-inverso, retro and inverso bifunctional peptides containing opioid peptide and CCK pharmacophores linked via a hydrazide moiety showed high δ and μ receptor binding affinities but weak CCK-1- and CCK-2 receptor binding affinities (Lee et al 2007). Antagonism of these peptides at CCK receptors was not demonstrated.…”

Section: Compounds With An Opioid Agonist/non-opioid Antagonist Profilementioning

confidence: 99%

Bi- or multifunctional opioid peptide drugs

2010

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Strategies for the design of bi-or multifunctional drugs are reviewed. A distinction is made between bifunctional drugs interacting in a monovalent fashion with two targets and ligands containing two distinct pharmacophores binding in a bivalent mode to the two binding sites in a receptor heterodimer. Arguments are presented to indicate that some of the so-called "bivalent" ligands reported in the literature are unlikely to simultaneously interact with two binding sites. Aspects related to the development of bi-or multifunctional drugs are illustrated with examples from the field of opioid analgesics. The drug-like properties of the tetrapeptide Dmt 1 [DALDA] with triple action as a μ opioid agonist, norepinephrine uptake inhibitor and releaser of endogenous opioid peptides to produce potent spinal analgesia are reviewed. Rationales for the development of opioid peptides with mixed agonist/antagonist profiles as analgesics with reduced side effects are presented. Progress in the development of mixed μ opioid agonist/δ opioid antagonists with low propensity to produce tolerance and physical dependence is reviewed. Efforts to develop bifunctional peptides containing a μ opioid agonist and a cholecystokinin antagonist or an NK1 receptor antagonist as analgesics expected to produce less tolerance and dependence are also reviewed. A strategy to improve the drug-like properties of bifunctional opioid peptide analgesics is presented.

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“…There is an increasing readiness to challenge the current paradigm and to consider developing agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single target [22–29]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

Vardanyan

Gokhale

Nichol

et al. 2009

Bioorganic & Medicinal Chemistry

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Acids 9 a–f as possible bivalent ligands designed as a structural combination of opioid μ-agonist (Fentanyl) and NSAID (Indomethacin) activities and produced compounds which were tested as analgesics. The obtained series of compounds exhibits low affinity and activity both at opioid receptors and as cyclooxygenase (COX) inhibitors. One explanation of the weak opioid activity could be stereochemical peculiarities of these bivalent compounds which differ significantly from the fentanyl skeleton. The absence of significant COX inhibitory properties could be explained by the required substitution of an acyl fragment in the indomethacin structure for 4-piperidyl.

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Partial Retro−Inverso, Retro, and Inverso Modifications of Hydrazide Linked Bifunctional Peptides for Opioid and Cholecystokinin (CCK) Receptors

Cited by 27 publications

References 18 publications

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Stability, toxicity and biological activity of retro, inversed and retro‐inversed glucagon isomers

Bi- or multifunctional opioid peptide drugs

Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain

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