Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

Remesic, Michael; Macedonio, Giorgia; Mollica, Adriano; Porreca, Frank; Hruby, Victor J.; Lee, Yeon Sun

doi:10.1016/j.bmc.2018.05.045

Cited by 6 publications

(6 citation statements)

References 21 publications

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“…Cyclic biphalin analogs through various linkers such as xylene were highly potent MOR/DOR agonists with prolonged analgesic effects after systemic administration [ 235 , 236 ]. Interestingly, a C -terminal-modified cyclic biphalin analog, c 2,2′ (Dmt- D Cys-Gly-Phe) 2 -cystamine, was a very potent MOR/DOR/KOR agonist with the sub-nanomolar affinities and the same high efficacies with DAMGO, DADLE, and salvinorin A at MOR, DOR, and KOR, respectively [ 237 ].…”

Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures.

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Section: Peptidomimetics For Opioid Receptorsmentioning

confidence: 99%

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Lee

2022

Biomolecules

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“…The latter is a dimeric enkephalin analog (Tyr-D-Ala-Gly-Phe-NH-)2 with high potency and affinity for MOR and DOR and low affinity for KOR. Biphalin crosses blood-brain barrier reaching spinal and supraspinal sites expressing OR and produces less physical dependence and tolerance compared to morphine [72,[81][82][83][84]. Table 2.…”

Section: The Opioid Systemmentioning

confidence: 99%

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

Mititelu-Tarțău¹,

Bogdan²,

Gheorman³

et al. 2019

Neuroprotection

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Due to brain plasticity, the nervous system is capable of manifesting behavioral variations, adapted to the influences from both external and internal environment. Multiple neurotransmitters are involved in the mediation of pathological processes at the molecular, cellular, regional, and interregional levels participating in cerebral plasticity, their intervention being responsible for various structural, functional, and behavioral disturbances. The current therapeutic strategies in neuroprotection aim at blocking on different levels, the molecular cascades of the pathophysiological mechanisms responsible for neuronal dysfunctions and ultimately for neuronal death. Different agents influencing these neurotransmitters have demonstrated beneficial effects in neurogenesis and neuroprotection, proved in experimental animal models of focal and global ischemic injuries. Serotonin, dopamine, glutamate, N-methyl-D-aspartate, and nitric oxide have been shown to play a significant role in modulating nervous system injuries. The imidazoline system is one of the important systems involved in human brain functioning. Experimental investigations have revealed the cytoprotective effects of imidazoline I2 receptor ligands against neuronal injury induced by hypoxia in experimental animals. The neuroprotective effects were also highlighted for kappa and delta receptors, whose agonists demonstrated the ability to reduce architectural lesions and to recover neuronal functions of animals with experimentally induced brain ischemia.

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“…Compound MACE4 , a cyclic analogue of biphalin incorporating the o -bis(methyl)benzene bridge, p -F-Phe 4,4′ and Dmt 1,1′ , possesses a high binding affinity for MOR/DOR and a moderate affinity for KOR, resulting in a full agonist at MOR and a partial agonist at DOR/KOR, with the best efficacy and in vivo antinociceptive activity of the series . The insertion of a Dmt residue in place on the native Tyr present in the analogue MACE2 seems to be crucial to determine a well-defined orientation of the side chains in the three-dimensional structure that fits the MOR binding site, thus producing a subnanomolar activity at MOR and also an improvement in KOR affinity. , …”

Section: Introductionmentioning

confidence: 99%

Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

Stefanucci

Minosi

Pieretti

et al. 2023

ACS Chem. Neurosci.

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The discovery of efficacious and safe analgesics with reduced side effects is the foremost challenge in the pain field. In this work, we report the in vitro and in vivo evaluation of linear and cyclic analogues of biphalin with the aim to complete the series of structural modifications previously applied in the development of opioid peptides incorporating a xylene bridge. Replacement of Tyr 1,1 ′ by Dmt (2,5-dimethyltyrosine) in the linear biphalin analogue AM94 and cyclic analogue MACE4 resulted in two new compounds (namely, MJ2 and MJ5) endowed with improved KOR/ MOR/DOR binding affinity. Both compounds showed a strong antinociceptive profile in in vivo models of nociception, allodynia, and hyperalgesia via the tail flick, hot plate, and formalin tests after intracerebroventricular and subcutaneous administration. One of these ligands, MJ2, was also tested in tolerance and dependence studies, exhibiting very little withdrawal symptoms.

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Cyclic biphalin analogues with a novel linker lead to potent agonist activities at mu, delta, and kappa opioid receptors

Cited by 6 publications

References 21 publications

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

Current Therapeutic Approaches from Imidazoline and Opioid Receptors Modulators in Neuroprotection

Design of Analgesic Trivalent Peptides with Low Withdrawal Symptoms: Probing the Antinociceptive Profile of Novel Linear and Cyclic Peptides as Opioid Pan Ligands

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