Design and Synthesis of Novel Hydrazide-Linked Bifunctional Peptides as δ/μ Opioid Receptor Agonists and CCK-1/CCK-2 Receptor Antagonists

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

doi:10.1021/jm050851n

Cited by 36 publications

(49 citation statements)

References 28 publications

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“…Compound 5 was synthesized using a previously reported method with minor modifications (32). 4mL of DMF was added to a flask containing 0.44 g (0.58 mmol, 1 equi) 4 and the solution was cooled to 0 °C.…”

Section: Methodsmentioning

confidence: 99%

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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CatalyCEST MRI can detect enzyme activity by monitoring the change in chemical exchange with water after a contrast agent is cleaved by an enzyme. Often these molecules use paramagnetic metals and are delivered with an additional non-responsive reference molecule. To improve this approach for molecular imaging, a single diamagnetic agent with enzyme-responsive and enzyme-unresponsive CEST signals was synthesized and characterized. The CEST signal from the aryl amide disappeared after cleavage of a dipeptidyl ligand with cathepsin B, while a salicylic acid moiety was largely unresponsive to enzyme activity. The ratiometric comparison of the two CEST signals from the same agent allowed for concentration independent measurements of enzyme activity. The chemical exchange rate of the salicylic acid moiety was unchanged after enzyme catalysis, which further validated that this moiety was enzyme-unresponsive. The temperature dependence of the chemical exchange rate of the salicylic acid moiety was non-Arrhenius, suggesting a two-step chemical exchange mechanism for salicylic acid. The good detection sensitivity at low saturation power facilitates clinical translation, along with the potentially low toxicity of a non-metallic MRI contrast agent. The modular design of the agent constitutes a platform technology that expands the variety of agents that may be employed by catalyCEST MRI for molecular imaging.

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Section: Methodsmentioning

confidence: 99%

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Hingorani

Montano

Randtke

et al. 2015

Contrast Media & Molecular

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“…18,20,35,36 The tissue bioassays (mouse vas deferens: MVD, guinea pig isolated ileum: GPI) also were performed to characterize agonist function at δ and μ opioid receptors as described previously (Table 4). 18,20,35,36 As for their affinity for the rat NK1 (rNK1) receptor, receptor binding assays also were used on transfected Chinese hamster ovary (CHO) cells that stably express rNK1 receptors using [ 3 H]-substance P as the standard radioligand (Table 2). To estimate their antagonistic activities against substance P stimulation, tissue bioassays using the guinea pig ileum (GPI) were performed in the presence of naloxone.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for δ/μ Opioid Receptor Agonists and Neurokinin-1 Receptor Antagonists

et al. 2007

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A series of bifunctional peptides that act as agonists for δ and μ opioid receptors with δ selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at δ/μ opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 (5) and H-Tyr-DAla-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF 3 ) 2 (7) had excellent agonist activity for both δ opioid and μ opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.

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“…12 (S)-1-(4-Fluorophenyl)-1-[3-(methylamino)propyl]-1,3-dihydroisobenzofuran-5-carbonitrile ( 1 , 1 mmol) and N α -Boc-amino acid (1.1 mmol) were dissolved in DMF (15 mL) and cooled in an ice bath for 10 minutes. HBTU (1.2 mmol) and DIEA (2 mmol) were added to the reaction mixture and stirred for 1–2 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…. 12–16 In our study, an enkephalin-based tetrapeptide, Tyr- D -Ala-Gly-Phe, and desmethylescitalopram ( 1 ) were used as an opioid agonist pharmacophore, and SSRIs pharmacophore, respectively.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

Mehr-un-Nisa

Munawar

Lee

et al. 2015

Bioorganic & Medicinal Chemistry

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A series of opioid and serotonin re-uptake inhibitors (SSRIs) bifunctional ligands have been designed, synthesized, and tested for their activities and efficacies at μ-, δ- and κ opioid receptors and SSRIs receptors. Most of the compounds showed high affinities for μ- and δ-opioid receptors and lower affinities for SSRIs and κ opioid receptors. A docking study on the μ-opioid receptor binding pocket has been carried out for ligands 3-11. The ligands 7 and 11 have displayed the highest binding profiles for the μ-opioid receptor binding site with ΔGbind (−12.14 kcal/mol) and Ki value (1.0 nM), and ΔGbind (−12.41 kcal/mol) and Ki value (0.4 nM), respectively. Ligand 3 was shown to have the potential of dual acting serotonin/norepinephrine re-uptake inhibitor (SNRI) antidepressant activity in addition to opioid activities, and thus could be used for the design of multifunctional ligands in the area of a novel approach for the treatment of pain and depression.

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Design and Synthesis of Novel Hydrazide-Linked Bifunctional Peptides as δ/μ Opioid Receptor Agonists and CCK-1/CCK-2 Receptor Antagonists

Cited by 36 publications

References 28 publications

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for δ/μ Opioid Receptor Agonists and Neurokinin-1 Receptor Antagonists

Design, synthesis, and biological evaluation of a series of bifunctional ligands of opioids/SSRIs

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