Low Molecular Weight Opioid Peptide Esters Could be Developed as a New Class of Analgesics

Goldberg, Jay

doi:10.4137/pmc.s6803

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…It is worth noting that analogues 5 and 6 with additional replacement of the Tyr 1 residue by Dmt were more stable compared with the related analogues 1–4. These results confirmed that cyclization protects peptides against enzymatic digestion and enhances their bioavailability. ,, Importantly, the replacement of the Tyr residue in position 1 by unnatural amino acid Dmt led to an additional enzymatic enhancement.…”

Section: Discussionsupporting

confidence: 64%

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Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Zhang

Wang

et al. 2021

J. Med. Chem.

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Endomorphins (EMs) are potent pharmaceuticals for the treatment of pain. Herein, we investigated several novel EM analogues with multiple modifications and oligoarginine conjugation. Our results showed that analogues 1–6 behaved as potent μ-opioid agonists and enhanced stability and lipophilicity. Analogues 5 and 6 administered centrally and peripherally induced significant and prolonged antinociceptive effects in acute pain. Both analogues also produced long-acting antiallodynic effects against neuropathic and inflammatory pain. Furthermore, they showed a reduced acute antinociceptive tolerance. Analogue 6 decreased the extent of chronic antinociceptive tolerance, and analogue 5 exhibited no tolerance at the supraspinal level. Particularly, they displayed nontolerance-forming antinociception at the peripheral level. In addition, analogues 5 and 6 exhibited reduced or no opioid-like side effects on gastrointestinal transit, conditioned place preference (CPP), and motor impairment. The present investigation established that multiple modifications and oligoarginine-vector conjugation of EMs would be helpful in developing novel analgesics with fewer side effects.

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Section: Discussionsupporting

confidence: 64%

“…These results confirmed that cyclization protects peptides against enzymatic digestion and enhances their bioavailability. 23,33,41 Importantly, the replacement of the Tyr residue in position 1 by unnatural amino acid Dmt led to an additional enzymatic enhancement.…”

Section: ■ Discussionmentioning

confidence: 99%

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Zhang

Wang

et al. 2021

J. Med. Chem.

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“…This leads to a cytotoxic intracellular acidosis that, together with the trapping of lactate and the consequential repression of its pro-invasive actions outside the cells, may eventually lead to a overall growth inhibition of the tumor. [340] …”

Section: Glycolytic Effectors As Potential Targets In Cancer Therapymentioning

confidence: 99%

Anticancer Agents That Counteract Tumor Glycolysis

2012

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Can we consider cancer as a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have to deal with increased needs for both energy and biosynthetic intermediates, in order to support their growth and invasiveness. However, their high proliferation rate often generates regions that are not sufficiently oxygenated. Therefore, their carbohydrate metabolism has to rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the “Warburg Effect”, constitutes a fundamental adaptation of the tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that anti-glycolytic agents may cause serious side effects on normal cells. Actually, the key for a selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anti-cancer drugs showing minimal toxicity. In fact, there is growing evidence that supports many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant anti-glycolytic agents that have been investigated so far for the treatment of cancer.

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“…S13 ). Based on Lipinski`s Rule for the central nervous system drugs (RoCNS), TAM B revealed closely CNS drug-likeness properties i.e., molecular weight = 433.170 (MW < 400), LogP = 3.081 (CLogP ≤ 5), a number of H-bond acceptor = 9 (HBA ≤ 7) and a number of H-bond donor = 4 (HBD ≤ 5) 47 , 48 . However, the topological polar surface area (TPSA) of compound 1 was 141.610 Å 2 which was higher than 90 Å 2 as a cut-off for optimal CNS exposure 49 .…”

Section: Resultsmentioning

confidence: 99%

New insights into the neuroprotective and beta-secretase1 inhibitor profiles of tirandamycin B isolated from a newly found Streptomyces composti sp. nov.

Duangupama

Pratuangdejkul

Chongruchiroj

et al. 2023

Sci Rep

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Tirandamycin (TAM B) is a tetramic acid antibiotic discovered to be active on a screen designed to find compounds with neuroprotective activity. The producing strain, SBST2-5T, is an actinobacterium that was isolated from wastewater treatment bio–sludge compost collected from Suphanburi province, Thailand. Taxonomic characterization based on a polyphasic approach indicates that strain SBST2-5T is a member of the genus Streptomyces and shows low average nucleotide identity (ANI) (81.7%), average amino-acid identity (AAI) (78.5%), and digital DNA-DNA hybridization (dDDH) (25.9%) values to its closest relative, Streptomyces thermoviolaceus NBRC 13905T, values that are significantly below the suggested cut-off values for the species delineation, indicating that strain SBST2-5T could be considered to represent a novel species of the genus Streptomyces. The analysis of secondary metabolites biosynthetic gene clusters (smBGCs) in its genome and chemical investigation led to the isolation of TAM B. Interestingly, TAM B at 20 µg/mL displayed a suppressive effect on beta-secretase 1 (BACE1) with 68.69 ± 8.84% inhibition. Molecular docking simulation reveals the interaction mechanism between TAM B and BACE1 that TAM B was buried in the pocket of BACE-1 by interacting with amino acids Thr231, Asp 228, Gln73, Lys 107 via hydrogen bond and Leu30, Tyr71, Phe108, Ile118 via hydrophobic interaction, indicating that TAM B represents a potential active BACE1 inhibitor. Moreover, TAM B can protect the neuron cells significantly (% neuron viability = 83.10 ± 9.83% and 112.72 ± 6.83%) from oxidative stress induced by serum deprivation and Aβ1–42 administration models at 1 ng/mL, respectively, without neurotoxicity on murine P19-derived neuron cells nor cytotoxicity against Vero cells. This study was reportedly the first study to show the neuroprotective and BACE1 inhibitory activities of TAM B.

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Low Molecular Weight Opioid Peptide Esters Could be Developed as a New Class of Analgesics

Cited by 10 publications

References 44 publications

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Novel Cyclic Endomorphin Analogues with Multiple Modifications and Oligoarginine Vector Exhibit Potent Antinociception with Reduced Opioid-like Side Effects

Anticancer Agents That Counteract Tumor Glycolysis

New insights into the neuroprotective and beta-secretase1 inhibitor profiles of tirandamycin B isolated from a newly found Streptomyces composti sp. nov.

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