Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted μ/δ/κ opioid receptor (2019–2022)

He, Ye; Su, Qian; Zhao, Liyun; Zhang, Lijuan; Yu, Lu; Shi, Jianyou

doi:10.1016/j.bioorg.2023.106869

Cited by 3 publications

(1 citation statement)

References 133 publications

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“…Because of the inadequate benefit/risk ratio of currently available opioids, together with the ongoing opioid epidemic, there is a huge quest for strategies to discover new opioid analgesics. Alternative chemical and pharmacological approaches are therefore explored to mitigate the deleterious effects of MOR agonists and to limit their abuse and misuse [9][10][11][12][13][14][15][16][17][18][19], amongst which are multifunctional drugs. The concept of 'one molecule, multiple targets' has received increased attention in opioid drug discovery as a promising strategy to generate new analgesics with enhanced effectiveness and reduced unwanted side effects.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

Hochrainer,

Serafin,

D’Ingiullo

et al. 2024

IJMS

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Diverse chemical and pharmacological strategies are currently being explored to minimize the unwanted side effects of currently used opioid analgesics while achieving effective pain relief. The use of multitarget ligands with activity at more than one receptor represents a promising therapeutic approach. We recently reported a bifunctional peptide-based hybrid LENART01 combining dermorphin and ranatensin pharmacophores, which displays activity to the mu-opioid receptor (MOR) and dopamine D2 receptor (D2R) in rat brains and spinal cords. In this study, we investigated the in vitro binding and functional activities to the human MOR and the in vivo pharmacology of LENART01 in mice after subcutaneous administration. In vitro binding assays showed LENART01 to bind and be selective to the human MOR over the other opioid receptor subtypes and delta, kappa and nociceptin receptors. In the [35S]GTPγS binding assay, LENART01 acted as a potent and full agonist to the human MOR. In mice, LENART01 produced dose-dependent antinociceptive effects in formalin-induced inflammatory pain, with increased potency than morphine. Antinociceptive effects were reversed by naloxone, indicating MOR activation in vivo. Behavioral studies also demonstrated LENART01’s properties to induce less adverse effects without locomotor dysfunction and withdrawal syndrome compared to conventional opioid analgesics, such as morphine. LENART01 is the first peptide-based MOR-D2R ligand known to date and the first dual MOR-dopamine D2R ligand for which in vivo pharmacology is reported with antinociceptive efficacy and reduced opioid-related side effects. Our current findings may pave the way to new pain therapeutics with limited side effects in acute and chronic use.

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Section: Introductionmentioning

confidence: 99%

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

Hochrainer,

Serafin,

D’Ingiullo

et al. 2024

IJMS

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Molecular docking of quercetin: a promising approach for the development of new anti-inflammatory and analgesic drugs

Ettitaou,

Kabdy,

Oubella

et al. 2024

Natural Product Research

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The aim of this study is to investigate the antinociceptive, anti-inflammatory and antipyretic effects of quercetin. Additionally, molecular docking studies were conducted to evaluate potential interactions between quercetin and various molecular targets. Animal models were used to conduct a comprehensive pharmacological investigation of quercetin. Evaluation of analgesic activity revealed a reduction in the number of abdominal cramps during the twisting test and inhibition of pain during the second phase of the formaldehyde test. Additionally, evaluation of its antiinflammatory activity showed a reduction in ear edema. However, it is important to note that quercetin administration has not been shown to significantly reduce yeast-induced hyperthermia.The docking study revealed the high inhibitory potential of quercetin against the COX-2 receptor.

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Morphinan Evolution: The Impact of Advances in Biochemistry and Molecular Biology

Kajino,

Tokuda,

Saitoh

2024

The Journal of Biochemistry

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Morphinan-based opioids, derived from natural alkaloids like morphine, codeine, and thebaine, have long been pivotal in managing severe pain. However, their clinical utility is marred by significant side effects and high addiction potential. This review traces the evolution of the morphinan scaffold in light of advancements in biochemistry and molecular biology, which have expanded our understanding of opioid receptor pharmacology. We explore the development of semi-synthetic and synthetic morphinans, their receptor selectivity, and the emergence of biased agonism as a strategy to dissociate analgesic properties from undesirable effects. By examining the molecular intricacies of opioid receptors and their signaling pathways, we highlight how receptor-type selectivity and signaling bias have informed the design of novel analgesics. This synthesis of historical and contemporary perspectives provides an overview of the morphinan landscape, underscoring the ongoing efforts to mitigate the problems facing opioids through smarter drug design. We also highlight that most morphinan derivatives show a preference for the G protein pathway, although detailed experimental comparisons are still necessary. This fact underscores the utility of the morphinan skeleton in future opioid drug discovery.

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Historical perspectives and recent advances in small molecule ligands of selective/biased/multi-targeted μ/δ/κ opioid receptor (2019–2022)

Cited by 3 publications

References 133 publications

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

In Vitro and In Vivo Pharmacological Profiles of LENART01, a Dermorphin–Ranatensin Hybrid Peptide

Molecular docking of quercetin: a promising approach for the development of new anti-inflammatory and analgesic drugs

Morphinan Evolution: The Impact of Advances in Biochemistry and Molecular Biology

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